rs2230414

chr11-64728885-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001098671.2(RASGRP2):c.1749C>A(p.Gly583=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,611,766 control chromosomes in the GnomAD database, including 13,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1636 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12315 hom.)
• Consequence: RASGRP2 NM_001098671.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.770

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 11-64728885-G-T is Benign according to our data. Variant chr11-64728885-G-T is described in ClinVar as [Benign]. Clinvar id is 403363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP2	NM_001098671.2	c.1749C>A	p.Gly583=	synonymous_variant	15/17	ENST00000394432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP2	ENST00000394432.8	c.1749C>A	p.Gly583=	synonymous_variant	15/17	1	NM_001098671.2	P4

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19775 AN: 152110 Hom.: 1633 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.155 AC: 38279 AN: 247532 Hom.: 3985 AF XY: 0.149 AC XY: 19980 AN XY: 134234

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.352

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0945

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.114 AC: 166771 AN: 1459538 Hom.: 12315 Cov.: 32 AF XY: 0.115 AC XY: 83582 AN XY: 726050

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.370

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0933

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.130 AC: 19809 AN: 152228 Hom.: 1636 Cov.: 32 AF XY: 0.136 AC XY: 10123 AN XY: 74430

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0992

Gnomad4 OTH AF: 0.140

Alfa AF: 0.112 Hom.: 1827

Bravo AF: 0.141

Asia WGS AF: 0.259 AC: 901 AN: 3478

EpiCase AF: 0.0990

EpiControl AF: 0.100

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	4.4
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230414; hg19: chr11-64496357; COSMIC: COSV62448948; COSMIC: COSV62448948;