NM_001098671.2:c.742G>T

Variant names:

• chr11-64739431-C-A
• rs587777529
• NM_001098671.2:c.742G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001098671.2(RASGRP2):​c.742G>T​(p.Gly248Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G248R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RASGRP2 NM_001098671.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86
• Publications: 13 publications found

Genes affected

RASGRP2 (HGNC:9879): (RAS guanyl releasing protein 2) 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]

RASGRP2 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 18

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteopetrosis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64739431-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1684408.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 11-64739431-C-A is Pathogenic according to our data. Variant chr11-64739431-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 139647.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP2	NM_001098671.2	c.742G>T	p.Gly248Trp	missense_variant	Exon 8 of 17	ENST00000394432.8	NP_001092141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP2	ENST00000394432.8	c.742G>T	p.Gly248Trp	missense_variant	Exon 8 of 17	1	NM_001098671.2	ENSP00000377953.3
RASGRP2	ENST00000445445.5	n.*443G>T		non_coding_transcript_exon_variant	Exon 8 of 8	5		ENSP00000396029.1
RASGRP2	ENST00000445445.5	n.*443G>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000396029.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Platelet-type bleeding disorder 18 Pathogenic:1

Jun 30, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;D;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;.;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	M;M;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.9	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.98
MutPred		0.73		Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);
MVP		0.57
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777529; hg19: chr11-64506903;