11-64727354-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R593C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: RASGRP2 NM_001098671.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.894

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 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	UniProt
RASGRP2	NM_001098671.2	c.1778G>A	p.Arg593His	missense_variant	16/17	ENST00000394432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP2	ENST00000394432.8	c.1778G>A	p.Arg593His	missense_variant	16/17	1	NM_001098671.2	P4

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152110 Hom.: 0 Cov.: 31

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: 79 AN: 251380 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135882

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.: 0 Cov.: 31 AF XY: 0.000751 AC XY: 546 AN XY: 727132

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: 70 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.000390 AC XY: 29 AN XY: 74438

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.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	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. -

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	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Benign	-0.061
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.86	D;.;.;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.51	T
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	T
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

Other links and lift over

dbSNP: rs149482849; hg19: chr11-64494826; COSMIC: COSV55454460; COSMIC: COSV55454460;