RASGRP2 (RAS guanyl releasing protein 2)

Gene

• Entrez ID: 10235
• Gene name: RAS guanyl releasing protein 2
• Gene symbol: RASGRP2
• Synonyms (NCBI Gene): CALDAG-GEFI, CDC25L
• Chromosome: 11
• Chromosome location: 11q13.1
• Summary: The protein encoded by this gene is a brain-enriched nucleotide exchanged factor that contains an N-terminal GEF domain, 2 tandem repeats of EF-hand calcium-binding motifs, and a C-terminal diacylglycerol/phorbol ester-binding domain. This protein can act

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs2959650	A>C	Likely-pathogenic	Splice donor variant, upstream transcript variant, genic upstream transcript variant
rs181901181	C>A,G,T	Uncertain-significance, conflicting-interpretations-of-pathogenicity	Intron variant
rs200434813	C>G,T	Likely-pathogenic	Coding sequence variant, missense variant, genic downstream transcript variant
rs374345558	C>G,T	Likely-pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant, synonymous variant
rs587777529	C>A,T	Pathogenic	Coding sequence variant, missense variant, genic downstream transcript variant
rs752492512	A>-	Likely-pathogenic	Frameshift variant, genic downstream transcript variant, coding sequence variant
rs774996406	C>-,CC	Likely-pathogenic	Coding sequence variant, frameshift variant, genic downstream transcript variant
rs781003927	G>A,C,T	Likely-pathogenic	Intron variant
rs1060499609	A>G	Conflicting-interpretations-of-pathogenicity	Missense variant, genic downstream transcript variant, downstream transcript variant, coding sequence variant
rs1555122100	->G	Likely-pathogenic	Coding sequence variant, frameshift variant, genic downstream transcript variant
rs1592371840	C>T	Likely-pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant
rs1592372097	T>C,G	Likely-pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant
rs1592372480	GACAAAGGACAG>-	Likely-pathogenic	Intron variant, genic downstream transcript variant
rs1592378730	A>G	Likely-pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant
rs1592379014	A>G	Likely-pathogenic	Missense variant, genic downstream transcript variant, coding sequence variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001558	Process	Regulation of cell growth	NAS	10918068
GO:0005085	Function	Guanyl-nucleotide exchange factor activity	IBA
GO:0005085	Function	Guanyl-nucleotide exchange factor activity	IDA	24958846
GO:0005085	Function	Guanyl-nucleotide exchange factor activity	IEA
GO:0005085	Function	Guanyl-nucleotide exchange factor activity	TAS	9789079
GO:0005509	Function	Calcium ion binding	IEA
GO:0005509	Function	Calcium ion binding	NAS	10918068
GO:0005509	Function	Calcium ion binding	TAS	9789079
GO:0005737	Component	Cytoplasm	IEA
GO:0005829	Component	Cytosol	IDA	10918068
GO:0005829	Component	Cytosol	IEA
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	IBA
GO:0005886	Component	Plasma membrane	IDA	10918068
GO:0005886	Component	Plasma membrane	IEA
GO:0007165	Process	Signal transduction	TAS	9789079
GO:0007264	Process	Small GTPase-mediated signal transduction	IEA
GO:0007265	Process	Ras protein signal transduction	IBA
GO:0007265	Process	Ras protein signal transduction	NAS	10918068
GO:0008270	Function	Zinc ion binding	IEA
GO:0008289	Function	Lipid binding	TAS	9789079
GO:0016020	Component	Membrane	IEA
GO:0019992	Function	Diacylglycerol binding	NAS	10918068
GO:0030695	Function	GTPase regulator activity	IEA
GO:0032587	Component	Ruffle membrane	IEA
GO:0042995	Component	Cell projection	IEA
GO:0043005	Component	Neuron projection	IEA
GO:0043547	Process	Positive regulation of GTPase activity	IDA	24958846
GO:0045202	Component	Synapse	IEA
GO:0046872	Function	Metal ion binding	IEA
GO:0071277	Process	Cellular response to calcium ion	IDA	24958846

Other IDs

• MIM: 605577
• HGNC: 9879
• e!Ensembl: ENSG00000068831

Protein

• UniProt ID: Q7LDG7
• Protein name: RAS guanyl-releasing protein 2 (Calcium and DAG-regulated guanine nucleotide exchange factor I) (CalDAG-GEFI) (Cdc25-like protein) (hCDC25L) (F25B3.3 kinase-like protein)
• Protein function: Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of
• PDB: 2MA2, 6AXF
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00618	RasGEF_N	9 → 103	RasGEF N-terminal motif	Domain
  PF00617	RasGEF	157 → 335	RasGEF domain	Family
  PF13202	EF-hand_5	461 → 485	EF hand	Domain
  PF00130	C1_1	499 → 551	Phorbol esters/diacylglycerol binding domain (C1 domain)	Domain

• Tissue specificity: TISSUE SPECIFICITY: Detected in platelets, neutrophils and T lymphocytes (at protein level). Expressed in brain where it is enriched in the striatum. Also expressed in the hematopoietic system. Detected in heart, brain, lung, placenta, liver, skeletal mus
• Sequence:

  MAGTLDLDKGCTVEELLRGCIEAFDDSGKVRDPQLVRMFLMMHPWYIPSSQLAAKLLHIY
  QQSRKDNSNSLQVKTCHLVRYWISAFPAEFDLNPELAEQIKELKALLDQEGNRRHSSLID
  IDSVPTYKWKRQVTQRNPVGQKKRKMSLLFDHLEPMELAEHLTYLEYRSFCKILFQDYHS
  FVTHGCTVDNPVLERFISLFNSVSQWVQLMILSKPTAPQRALVITHFVHVAEKLLQLQNF
  NTLMAVVGGLSHSSISRLKETHSHVSPETIKLWEGLTELVTATGNYGNYRRRLAACVGFR
  FPILGVHLKDLVALQLALPDWLDPARTRLNGAKMKQLFSILEELAMVTSLRPPVQANPDL
  LSLLTVSLDQYQTEDELYQLSLQREPRSKSSPTSPTSCTPPPRPPVLEEWTSAAKPKLDQ
  ALVVEHIEKMVESVFRNFDVDGDGHISQEEFQIIRGNFPYLSAFGDLDQNQDGCISREEM
  VSYFLRSSSVLGGRMGFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQC
  KDRLSVECRRRAQSVSLEGSAPSPSPMHSHHHRAFSFSLPRPGRRGSRPPEIREEEVQTV
  EDGVFDIHL

• Sequence length: 609

Pathways

KEGG:

MAPK signaling pathway
Ras signaling pathway
Rap1 signaling pathway
Chemokine signaling pathway
Platelet activation
Pathways in cancer

Reactome:

Integrin signaling
Rap1 signalling

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
Abnormal bleeding	Likely pathogenic	rs1592371840	RCV000852247	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Abnormal platelet aggregation	Likely pathogenic; Pathogenic	rs752492512, rs374345558, rs1592371840, rs1592372097, rs1592378730, rs1592379014, rs1592372480, rs781003927, rs2959650	RCV000851699 RCV000851925 RCV000851953 RCV000851906 RCV000852213 RCV000852192 RCV000852226 RCV000851981 RCV000851748	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Platelet-type bleeding disorder 18	Pathogenic; Likely pathogenic	rs587777529, rs2135765010, rs1592384832, rs767965347, rs2135780423, rs1555122100, rs752492512, rs1592371840, rs774996406, rs200434813	RCV000128611 RCV002223120 RCV002223121 RCV002223122 RCV002226407 RCV002245414 RCV000477816 RCV001003526 RCV002280888 RCV001003527 RCV001003528	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
RASGRP2-related disorder	Likely pathogenic; Pathogenic	rs2496490002, rs752492512	RCV003971808 RCV003411706	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Acute myeloid leukemia	Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BERNARD-SOULIER GIANT PLATELET SYNDROME	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER DUE TO CALDAG-GEFI DEFICIENCY	—	Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER DUE TO DEFICIENCY OF CALCIUM AND DIACYLGLYCEROL-REGULATED GUANINE NUCLEOTIDE EXCHANGE FACTOR I	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	—	CTD, Disgenet, HPO CTD, Disgenet, HPO CTD, Disgenet, HPO	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cervical cancer	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cholangiocarcinoma	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Clear cell carcinoma of kidney	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DESBUQUOIS SYNDROME	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Gastric cancer	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
GOUT	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
GRAY PLATELET SYNDROME	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HYPERURICEMIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of esophagus	Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
OSTEOPETROSIS	—	Disgenet, GenCC Disgenet, GenCC	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Ovarian serous cystadenocarcinoma	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
THROMBASTHENIA	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
THROMBOASTHENIA	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thrombocytopenia	Uncertain significance	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Thymoma	Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Anemia	Anemia	Pubtator	39512176	Associate	★☆☆☆☆ Found in Text Mining only
Arthritis	Arthritis	BEFREE	30076153		★☆☆☆☆ Found in Text Mining only
Bleeding disorder due to CalDAG-GEFI deficiency	Bleeding Disorder	Orphanet			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	Platelet-type bleeding disorder	CLINGEN_DG	15334074, 17576779, 24958846, 27235135, 27417588, 27663674, 28637664, 28762304, 9789079		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	Platelet-type bleeding disorder	GENOMICS_ENGLAND_DG	18709451, 28762304		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	Platelet-type bleeding disorder	UNIPROT_DG	24958846, 27235135, 28726538, 28762304		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	Platelet-type bleeding disorder	ORPHANET_DG	24958846		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	Platelet-type bleeding disorder	CLINVAR_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BLEEDING DISORDER, PLATELET-TYPE, 18	Platelet-type bleeding disorder	CTD_human_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Blood Coagulation Disorders	Blood Coagulation Disorders	BEFREE	27235135, 28726538, 28762304, 30849270, 31724816		★☆☆☆☆ Found in Text Mining only
Blood Platelet Disorders	Platelet-type bleeding disorder	BEFREE	26164464		★☆☆☆☆ Found in Text Mining only
Blood Platelet Disorders	Platelet disorder	Pubtator	27235135, 30849270, 39512176	Associate	★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	25901761		★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	32148377	Associate	★☆☆☆☆ Found in Text Mining only
Chronic Lymphocytic Leukemia	Lymphocytic Leukemia	BEFREE	29970392		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	32908876	Associate	★☆☆☆☆ Found in Text Mining only
Degenerative polyarthritis	Arthritis	BEFREE	30076153		★☆☆☆☆ Found in Text Mining only
Hemorrhage	Hemorrhage	Pubtator	24958846, 30849270, 32609603	Associate	★☆☆☆☆ Found in Text Mining only
Hemorrhagic Disorders	Hemorrhagic disease	Pubtator	27235135	Associate	★☆☆☆☆ Found in Text Mining only
Leukocyte adhesion deficiency type 1	Leukocyte adhesion deficiency	Pubtator	19234463	Associate	★☆☆☆☆ Found in Text Mining only
Leukocyte Adhesion Deficiency, Type III	Leukocyte adhesion deficiency	BEFREE	31724816		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	25901761		★☆☆☆☆ Found in Text Mining only
Multiple Sclerosis	Multiple sclerosis	Pubtator	30173916	Associate	★☆☆☆☆ Found in Text Mining only
Rheumatoid Arthritis	Rheumatoid arthritis	BEFREE	30076153		★☆☆☆☆ Found in Text Mining only
Thrombasthenia	Thrombasthenia	Pubtator	27235135	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thrombosis	Thrombosis	Pubtator	24958846	Associate	★☆☆☆☆ Found in Text Mining only
Vascular Malformations	Vascular malformation	Pubtator	39512176	Associate	★☆☆☆☆ Found in Text Mining only
Von Willebrand disease platelet type	Von willebrand disorder	Pubtator	32609603	Associate	★☆☆☆☆ Found in Text Mining only