CNKSR2 (connector enhancer of kinase suppressor of Ras 2)

Gene

• Entrez ID: 22866
• Gene name: Connector enhancer of kinase suppressor of Ras 2
• Gene symbol: CNKSR2
• Synonyms (NCBI Gene): CNK2, KSR2, MAGUIN, MRXSHG
• Chromosome: X
• Chromosome location: Xp22.12
• Summary: This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may als

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs113091231	G>A	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant
rs606231282	->A	Pathogenic	Frameshift variant, coding sequence variant
rs760890681	A>G	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant
rs886041712	G>-	Pathogenic	Frameshift variant, coding sequence variant
rs886041798	CTTAC>-	Pathogenic	Frameshift variant, coding sequence variant
rs904072058	C>A,T	Pathogenic	Synonymous variant, stop gained, coding sequence variant
rs1064793729	G>A	Pathogenic	Splice donor variant
rs1064794022	C>A,T	Pathogenic	Synonymous variant, coding sequence variant, stop gained
rs1555941759	G>C	Likely-pathogenic	Splice donor variant
rs1569261319	G>A	Pathogenic	Coding sequence variant, stop gained
rs1601952572	->C	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1602013845	AG>-	Pathogenic	Coding sequence variant, frameshift variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT538461	hsa-miR-4662a-3p	PAR-CLIP	22012620
MIRT538460	hsa-miR-203b-5p	PAR-CLIP	22012620
MIRT538459	hsa-miR-6718-5p	PAR-CLIP	22012620
MIRT538458	hsa-miR-140-5p	PAR-CLIP	22012620
MIRT538457	hsa-miR-6847-3p	PAR-CLIP	22012620
MIRT538456	hsa-miR-5681b	PAR-CLIP	22012620
MIRT538455	hsa-miR-7973	PAR-CLIP	22012620
MIRT538454	hsa-miR-4460	PAR-CLIP	22012620
MIRT538453	hsa-miR-6808-3p	PAR-CLIP	22012620
MIRT538452	hsa-miR-758-3p	PAR-CLIP	22012620
MIRT538461	hsa-miR-4662a-3p	PAR-CLIP	22012620
MIRT538460	hsa-miR-203b-5p	PAR-CLIP	22012620
MIRT538459	hsa-miR-6718-5p	PAR-CLIP	22012620
MIRT538458	hsa-miR-140-5p	PAR-CLIP	22012620
MIRT538457	hsa-miR-6847-3p	PAR-CLIP	22012620
MIRT538456	hsa-miR-5681b	PAR-CLIP	22012620
MIRT538455	hsa-miR-7973	PAR-CLIP	22012620
MIRT538454	hsa-miR-4460	PAR-CLIP	22012620
MIRT538453	hsa-miR-6808-3p	PAR-CLIP	22012620
MIRT538452	hsa-miR-758-3p	PAR-CLIP	22012620
MIRT899737	hsa-miR-1911	CLIP-seq
MIRT899738	hsa-miR-3173-3p	CLIP-seq
MIRT899739	hsa-miR-381	CLIP-seq
MIRT899740	hsa-miR-4666-3p	CLIP-seq
MIRT899741	hsa-miR-584	CLIP-seq
MIRT899742	hsa-miR-634	CLIP-seq
MIRT899743	hsa-miR-759	CLIP-seq
MIRT899744	hsa-miR-186	CLIP-seq
MIRT899745	hsa-miR-27a	CLIP-seq
MIRT899746	hsa-miR-27b	CLIP-seq
MIRT899747	hsa-miR-4698	CLIP-seq
MIRT899748	hsa-miR-4719	CLIP-seq
MIRT899749	hsa-miR-513a-5p	CLIP-seq
MIRT899750	hsa-miR-369-3p	CLIP-seq
MIRT899751	hsa-miR-374a	CLIP-seq
MIRT899752	hsa-miR-374b	CLIP-seq
MIRT899739	hsa-miR-381	CLIP-seq
MIRT899740	hsa-miR-4666-3p	CLIP-seq
MIRT899739	hsa-miR-381	CLIP-seq
MIRT899740	hsa-miR-4666-3p	CLIP-seq
MIRT899739	hsa-miR-381	CLIP-seq
MIRT899740	hsa-miR-4666-3p	CLIP-seq
MIRT1966894	hsa-miR-21	CLIP-seq
MIRT1966895	hsa-miR-590-5p	CLIP-seq
MIRT899739	hsa-miR-381	CLIP-seq
MIRT899740	hsa-miR-4666-3p	CLIP-seq
MIRT2505573	hsa-miR-539	CLIP-seq
MIRT2505574	hsa-miR-758	CLIP-seq
MIRT2505573	hsa-miR-539	CLIP-seq
MIRT2505574	hsa-miR-758	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0005515	Function	Protein binding	IPI	18287031, 27956147
GO:0005737	Component	Cytoplasm	IEA
GO:0005886	Component	Plasma membrane	IDA	14597674
GO:0009966	Process	Regulation of signal transduction	IEA
GO:0014069	Component	Postsynaptic density	IEA
GO:0016020	Component	Membrane	IEA
GO:0019901	Function	Protein kinase binding	IDA	14597674
GO:0035556	Process	Intracellular signal transduction	IDA	14597674
GO:0042802	Function	Identical protein binding	IEA
GO:0043025	Component	Neuronal cell body	IEA
GO:0045211	Component	Postsynaptic membrane	IEA
GO:0070062	Component	Extracellular exosome	HDA	19056867
GO:0098978	Component	Glutamatergic synapse	IEA
GO:0099084	Process	Postsynaptic specialization organization	IEA
GO:0099147	Component	Extrinsic component of postsynaptic density membrane	IEA
GO:0099173	Process	Postsynapse organization	IEA

Other IDs

• MIM: 300724
• HGNC: 19701
• e!Ensembl: ENSG00000149970

Protein

• UniProt ID: Q8WXI2
• Protein name: Connector enhancer of kinase suppressor of ras 2 (Connector enhancer of KSR 2) (CNK homolog protein 2) (CNK2)
• Protein function: May function as an adapter protein or regulator of Ras signaling pathways.
• PDB: 2EAN, 3BS5
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00536	SAM_1	9 → 73	SAM domain (Sterile alpha motif)	Domain
  PF10534	CRIC_ras_sig	84 → 176	Connector enhancer of kinase suppressor of ras	Domain
  PF00595	PDZ	216 → 294	PDZ domain	Domain
  PF06663	DUF1170	339 → 497	Protein of unknown function (DUF1170)	Family
  PF00169	PH	571 → 669	PH domain	Domain

• Sequence:

  MALIMEPVSKWSPSQVVDWMKGLDDCLQQYIKNFEREKISGDQLLRITHQELEDLGVSRI
  GHQELILEAVDLLCALNYGLETENLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKL
  PNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQLCLELTTIVQQDCTVYET
  ENKILHVCKTLSGVCDHIISLSSDPLVSQSAHLEVIQLANIKPSEGLGMYIKSTYDGLHV
  ITGTTENSPADRCKKIHAGDEVIQVNHQTVVGWQLKNLVNALREDPSGVILTLKKRPQSM
  LTSAPALLKNMRWKPLALQPLIPRSPTSSVATPSSTISTPTKRDSSALQDLYIPPPPAEP
  YIPRDEKGNLPCEDLRGHMVGKPVHKGSESPNSFLDQEYRKRFNIVEEDTVLYCYEYEKG
  RSSSQGRRESTPTYGKLRPISMPVEYNWVGDYEDPNKMKRDSRRENSLLRYMSNEKIAQE
  EYMFQRNSKKDTGKKSKKKGDKSNSPTHYSLLPSLQMDALRQDIMGTPVPETTLYHTFQQ
  SSLQHKSKKKNKGPIAGKSKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKD
  ASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFKACHPKIKSFYFAAEHLDDMNRW
  LNRINMLTAGYAERERIKQEQDYWSESDKEEADTPSTPKQDSPPPPYDTYPRPPSMSCAS
  PYVEAKHSRLSSTETSQSQSSHEEFRQEVTGSSAVSPIRKTASQRRSWQDLIETPLTSSG
  LHYLQTLPLEDSVFSDSAAISPEHRRQSTLPTQKCHLQDHYGPYPLAESERMQVLNGNGG
  KPRSFTLPRDSGFNHCCLNAPVSACDPQDDVQPPEVEEEEEEEEEEGEAAGENIGEKSES
  REEKLGDSLQDLYRALEQASLSPLGEHRISTKMEYKLSFIKRCNDPVMNEKLHRLRILKS
  TLKAREGEVAIIDKVLDNPDLTSKEFQQWKQMYLDLFLDICQNTTSNDPLSISSEVDVIT
  SSLAHTHSYIETHV

• Sequence length: 1034

Pathways

Reactome:

MAP2K and MAPK activation
Signaling by moderate kinase activity BRAF mutants
Signaling by high-kinase activity BRAF mutants
Signaling by BRAF and RAF fusions
Paradoxical activation of RAF signaling by kinase inactive BRAF
Signaling downstream of RAS mutants

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Intellectual disability	Likely pathogenic; Pathogenic	rs1569161831, rs2092480152	RCV000760277 RCV001260689	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Intellectual disability, X-linked, syndromic, Houge type	Pathogenic; Likely pathogenic	rs2147123782, rs2147268813, rs2147283343, rs2147191275, rs606231282, rs2147143428, rs2519101342, rs1602013845, rs2519358174, rs2519083192, rs2519299753, rs904072058, rs1569261319, rs2092480172, rs2092414327	RCV001375874 RCV001638189 RCV001728040 RCV001780796 RCV000144938 RCV002267688 RCV002465470 RCV002470212 RCV003228738 RCV003318474 RCV003448921 RCV000516164 RCV000785133 RCV001253675 RCV001291713	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Neurodevelopmental disorder	Likely pathogenic	rs1569272271	RCV000782047	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
X-linked recessive seizure and neurodevelopmental deficit	Likely pathogenic	rs1555941759	RCV000578363	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
ATTENTION DEFICIT HYPERACTIVITY DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
AUTISM SPECTRUM DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BIPOLAR DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cervical cancer	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CNKSR2-related disorder	Likely benign; Benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIABETES MELLITUS, NON-INSULIN-DEPENDENT	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIABETES MELLITUS, TYPE 2	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
INSOMNIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, HOUGE TYPE	—	Disgenet, HPO Disgenet, HPO	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MAJOR DEPRESSIVE DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MENTAL RETARDATION, X-LINKED NONSYNDROMIC	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
NEURODEVELOPMENTAL DISORDERS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
NON-SPECIFIC EARLY-ONSET EPILEPTIC ENCEPHALOPATHY	—	Disgenet, Orphanet Disgenet, Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
NON-SYNDROMIC X-LINKED INTELLECTUAL DISABILITY	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
POST-TRAUMATIC STRESS DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PSYCHIATRIC DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SCHIZOPHRENIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thyroid cancer, nonmedullary, 1	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TYPE 2 DIABETES MELLITUS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
UNDETERMINED EARLY-ONSET EPILEPTIC ENCEPHALOPATHY	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
X-LINKED COMPLEX NEURODEVELOPMENTAL DISORDER	—	ClinGen, GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
X-LINKED NON-SYNDROMIC INTELLECTUAL DISABILITY	—	Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
2-3 toe syndactyly	Syndactyly Of The Toes	HPO_DG			★☆☆☆☆ Found in Text Mining only
Aphasia	Aphasia	BEFREE	28098945		★☆☆☆☆ Found in Text Mining only
Apraxias	Apraxia	Pubtator	37929438	Associate	★☆☆☆☆ Found in Text Mining only
Attention Deficit Disorder with Hyperactivity	Attention deficit hyperactivity disorder	Pubtator	33298018	Associate	★☆☆☆☆ Found in Text Mining only
Attention deficit hyperactivity disorder	Attention Deficit Hyperactivity Disorder	HPO_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Autistic behavior	Autism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Autistic Disorder	Autism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Blepharoptosis	Ptosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	29534682		★☆☆☆☆ Found in Text Mining only
Breast Neoplasms	Breast neoplasm	Pubtator	29534682	Associate	★☆☆☆☆ Found in Text Mining only
Cerebral atrophy	Cerebral Atrophy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	UNIPROT_DG			★☆☆☆☆ Found in Text Mining only
Developmental Disabilities	Developmental disability	Pubtator	33298018	Associate	★☆☆☆☆ Found in Text Mining only
Developmental regression	Developmental regression	HPO_DG			★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	GWASCAT_DG	30718926		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	CTD_human_DG	30718926		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Dwarfism	Dwarfism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Dyskinetic syndrome	Dyskinetic Syndrome	HPO_DG			★☆☆☆☆ Found in Text Mining only
Encephalopathies	Epileptic encephalopathy	BEFREE	30126759		★☆☆☆☆ Found in Text Mining only
Encephalopathies	Epileptic encephalopathy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Epilepsy	Epilepsy	BEFREE	28098945, 31414730		★☆☆☆☆ Found in Text Mining only
Epilepsy	Epilepsy	Pubtator	31414730, 33298018, 34114993	Associate	★☆☆☆☆ Found in Text Mining only
Facial paralysis	Facial paralysis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Gastroesophageal reflux disease	Gastroesophageal Reflux Disease	HPO_DG			★☆☆☆☆ Found in Text Mining only
Global developmental delay	Developmental Delay	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hyperkinesis	Hyperkinesia	Pubtator	34114993	Associate	★☆☆☆☆ Found in Text Mining only
Hypodontia	Hypodontia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Intellectual Disability	Intellectual developmental disorder	Pubtator	23871722, 31414730, 34114993, 37929438	Associate	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Intellectual Disability	Mental retardation	BEFREE	31414730		★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Intellectual Disability	Mental retardation	HPO_DG			★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Invasive Ductal Breast Carcinoma	Invasive Duct and Lobular Carcinoma	BEFREE	29534682		★☆☆☆☆ Found in Text Mining only
Language Disorders	Language development disorders	Pubtator	33298018, 34114993	Associate	★☆☆☆☆ Found in Text Mining only
Macrocephaly	Macrocephaly	HPO_DG			★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	29534682		★☆☆☆☆ Found in Text Mining only
Meckel Diverticulum	Meckel Diverticulum	HPO_DG			★☆☆☆☆ Found in Text Mining only
Mental Retardation	Mental retardation	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Mental Retardation, X-Linked 1	Mental Retardation, X-Linked	ORPHANET_DG	25644381		★☆☆☆☆ Found in Text Mining only
Mental Retardation, X-Linked, Syndromic, Christianson Type	Mental retardation	BEFREE	30126759		★☆☆☆☆ Found in Text Mining only
MENTAL RETARDATION, X-LINKED, SYNDROMIC, HOUGE TYPE	Mental retardation	GENOMICS_ENGLAND_DG	28098945		★☆☆☆☆ Found in Text Mining only
MENTAL RETARDATION, X-LINKED, SYNDROMIC, HOUGE TYPE	Mental retardation	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Microcephaly	Microcephaly	HPO_DG			★☆☆☆☆ Found in Text Mining only
Mild Mental Retardation	Mental retardation	BEFREE	31414730		★☆☆☆☆ Found in Text Mining only
Mild neurosensory hearing impairment	Neurosensory Hearing impairment	HPO_DG			★☆☆☆☆ Found in Text Mining only
Moderate intellectual disability	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
nervous system disorder	Nervous System Disorder	BEFREE	25223753		★☆☆☆☆ Found in Text Mining only
Non-specific early-onset epileptic encephalopathy	Non-Specifi Epileptic Encephalopathy	Orphanet			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Nystagmus	Nystagmus	HPO_DG			★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	HPO_DG			★☆☆☆☆ Found in Text Mining only
Optic Atrophy	Optic Atrophy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Ptosis	Ptosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Seizures	Seizures	Pubtator	31414730	Associate	★☆☆☆☆ Found in Text Mining only
Severe intellectual disability	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Status Epilepticus	Status Epilepticus	HPO_DG			★☆☆☆☆ Found in Text Mining only
Tonic - clonic seizures	Seizure	HPO_DG			★☆☆☆☆ Found in Text Mining only
X-linked non-syndromic intellectual disability	Non-Syndromic Intellectual Disability, X-Linked	Orphanet			★★☆☆☆ Found in Text Mining + Unknown/Other Associations