RASGRP2

protein-coding

RAS guanyl releasing protein 2, the group of EF-hand domain containing

Gene 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 activate small GTPases, including RAS and RAP1/RAS3. The nucleotide exchange activity of this protein can be stimulated by calcium and diacylglycerol. Four alternatively spliced transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

MANE transcript

NM_001098671.2

Inheritance

ClinVar variants

P:31U:118B:83

Top phenotype

Bleeding disorder, platelet-type, 18

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr11:64,726,911-64,745,456

External References & Databases

Ensembl (ENSG00000068831)

Transcript & Mutation Effects

hg38 • Region Span ~18.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteopetrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0017198

Submitter: Genomics England PanelApp

platelet-type bleeding disorder 18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014386

Submitter: LiferaOmics

ClinGen RASGRP2– related Bleeding disorder, platelet-type, 18 – Definitive – Approval Date: 09/27/2019 ClinGen Evidence Breakdown Genetic Evidence = 12.0 points (max reached) Based on: • PMID: 24958846 • PMID: 27235135 • PMID: 28637664 • PMID: 27663674 • PMID: 28762304 Experimental Evidence = 6.0 points (max reached) Based on: • PMID: 24958846 – Functional studies demonstrating defective Rap1 activation and impaired integrin αIIbβ3 activation in patient platelets • PMID: 27235135 – Platelet functional assays confirming defective aggregation and signaling • PMID: 28637664 – Mechanistic studies supporting CalDAG-GEFI role in platelet activation pathway • Additional publications including in vivo mouse model and rescue data supporting platelet dysfunction phenotype ClinGen Total = 18.0 Genetic Evidence – Our Case Family 1 – one proband. Case-level (biallelic non-LOF/splice-region variant in AR model; homozygous; consanguinity unknown so no deduction applied) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Our Case Total = 1.0 / 12 Updated Total Genetic Evidence (ClinGen + Our Case) ClinGen genetic evidence: 12.0 (cap reached) Our additional case: 1.0 Updated genetic total = 12.0 (cap maintained) Experimental Evidence (unchanged from ClinGen) ClinGen experimental evidence = 6.0 Updated Overall Score Genetic evidence = 12.0 Experimental evidence = 6.0 Updated total = 18.0

platelet-type bleeding disorder 18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014386

Submitter: ClinGen

RASGRP2 was first reported in relation to autosomal recessive platelet-type bleeding disorder 18 in 2014 (Canault et al., PMID: 24958846). At least 20 unique variants (including mostly missense, as well as nonsense, and a few splicing and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 13 probands in 5 publications (PMIDs: 24958846, 27235135, 28637664, 27663674, 28762304). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the protein function in integrin activation, functional alteration and rescue in patient cells, and mouse models (including a knockout mouse and a humanized knock-in partial rescue). In summary, RASGRP2 is definitively associated with autosomal recessive platelet-type bleeding disorder 18. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene was previously implicated to be associated with leukocyte adhesion deficiency-3 (LAD3) (PMID:17576779), however it was later shown (PMIDs:19064721, 19234463, and 19234460) to not be the case and LAD3 is associated with defects in the FERMT3 gene.

platelet-type bleeding disorder 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014386

Submitter: PanelApp Australia

platelet-type bleeding disorder 18SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014386

Submitter: Orphanet

platelet-type bleeding disorder 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014386

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Bleeding disorder, platelet-type, 18AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals may demonstrate a bleeding diathesis (including postraumatic/postsurgical), and surveillance and prompt treatment of bleeding episodes may be beneficial

Refs: 24958846

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RASGRP2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 207

Inborn genetic diseasesTotal: 67

not specifiedTotal: 39

RASGRP2-related disorderTotal: 18

Platelet-type bleeding disorder 18Total: 15

Abnormal platelet aggregationTotal: 9

Abnormal bleedingTotal: 3

ThrombocytopeniaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001098671.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	73 clinvar	4 clinvar	79
missense	2 clinvar	10 clinvar	114 clinvar	6 clinvar		132
nonsense	4 clinvar		2 clinvar			6
start loss						0
frameshift	7 clinvar	3 clinvar				10
splice donor/acceptor (+/-2bp)		5 clinvar				5
Total	13	18	118	79	4	232

Highest pathogenic variant AF is 0.000047067562

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 106 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001098671.2	RefSeq	NP_001092141.1	15	MANE Select
ENST00000394432.8	Ensembl	ENSP00000377953.3	15	MANE Select
NM_001098670.2	RefSeq	NP_001092140.1	15	Standard
NM_001318398.2	RefSeq	NP_001305327.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
Chemokine signaling pathway - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)

Biological Process

regulation of cell growth
signal transduction
Ras protein signal transduction
positive regulation of GTPase activity
cellular response to calcium ion

Molecular Function

guanyl-nucleotide exchange factor activity
calcium ion binding
lipid binding
diacylglycerol binding

Cellular Component

cytosol
plasma membrane
cell junction
ruffle membrane
neuron projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354024
Coding exons: 15
Length: 18546
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125747
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	294	375	0.784	0.0000255	3948
Missense (PolyPhen)		87	113.98	0.76327		1187
Synonymous	0.445	146	153	0.954	0.00000992	1202
Loss of Function	3.83	7	29.4	0.238	0.00000155	330

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activates other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation. May function in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway. {ECO:0000269|PubMed:10918068, ECO:0000269|PubMed:14702343, ECO:0000269|PubMed:17576779, ECO:0000269|PubMed:17702895, ECO:0000269|PubMed:24958846, ECO:0000269|PubMed:27235135}.;
Disease: DISEASE: Bleeding disorder, platelet-type 18 (BDPLT18) [MIM:615888]: A disorder characterized by increased bleeding tendency due to platelet dysfunction. Clinical features include epistaxis, hematomas, bleeding after tooth extraction, and menorrhagia. {ECO:0000269|PubMed:24958846, ECO:0000269|PubMed:27235135, ECO:0000269|PubMed:28726538, ECO:0000269|PubMed:28762304}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.152

Intolerance Scores

LoFtool: 0.341
RVIS EVS: -0.8
RVIS percentile EVS: 12.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.895

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium