11-64727354-C-T

Position:

chr11-64727354-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001098671.2(RASGRP2):c.1778G>A(p.Arg593His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00081 ( 0 hom. )

Consequence

RASGRP2
NM_001098671.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.894

Variant links:

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 links:

RASGRP2 (HGNC:):

RASGRP2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040214896).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00046 (70/152228) while in subpopulation NFE AF= 0.000912 (62/68004). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP2	NM_001098671.2 linkuse as main transcript	c.1778G>A	p.Arg593His	missense_variant	16/17	ENST00000394432.8	NP_001092141.1	Q7LDG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRP2	ENST00000394432.8 linkuse as main transcript	c.1778G>A	p.Arg593His	missense_variant	16/17	1	NM_001098671.2	ENSP00000377953.3		Q7LDG7-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000912

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000314

AC:

AN:

251380

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000642

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000811

AC:

1186

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

546

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00100

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.000460

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000912

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000501

Hom.:

Bravo

AF:

0.000453

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 593 of the RASGRP2 protein (p.Arg593His). This variant is present in population databases (rs149482849, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RASGRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 594472). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 30, 2024

Variant summary: RASGRP2 c.1778G>A (p.Arg593His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251380 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RASGRP2 causing Platelet-Type Bleeding Disorder 18, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1778G>A in individuals affected with Platelet-Type Bleeding Disorder 18 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 594472). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1778G>A (p.R593H) alteration is located in exon 16 (coding exon 15) of the RASGRP2 gene. This alteration results from a G to A substitution at nucleotide position 1778, causing the arginine (R) at amino acid position 593 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

.;T;T;T

Eigen

Benign

-0.061

Eigen_PC

Benign

0.046

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.86

D;.;.;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.34

.;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.069

Sift

Uncertain

0.012

D;D;D;D

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.90

.;P;P;P

Vest4

0.29

MVP

0.29

MPC

0.76

ClinPred

0.062

GERP RS

3.6

Varity_R

0.11

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over