11-64729273-G-A

Variant names:

• chr11-64729273-G-A
• rs72927040
• NM_001098671.2:c.1592-231C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001098671.2(RASGRP2):​c.1592-231C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 152,020 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.019 (41 hom., cov: 32)
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.878

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-64729273-G-A is Benign according to our data. Variant chr11-64729273-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1209257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0188 (2851/152020) while in subpopulation NFE AF = 0.0278 (1888/67996). AF 95% confidence interval is 0.0267. There are 41 homozygotes in GnomAd4. There are 1305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP2	NM_001098671.2	c.1592-231C>T		intron_variant	Intron 14 of 16	ENST00000394432.8	NP_001092141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP2	ENST00000394432.8	c.1592-231C>T		intron_variant	Intron 14 of 16	1	NM_001098671.2	ENSP00000377953.3

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2852 AN: 151926 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00588

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.00693

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0188 AC: 2851 AN: 152020 Hom.: 41 Cov.: 32 AF XY: 0.0176 AC XY: 1305 AN XY: 74294

African (AFR) AF: 0.00589 AC: 244 AN: 41460

American (AMR) AF: 0.0172 AC: 262 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 260 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00791 AC: 38 AN: 4802

European-Finnish (FIN) AF: 0.00693 AC: 73 AN: 10534

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0278 AC: 1888 AN: 67996

Other (OTH) AF: 0.0204 AC: 43 AN: 2106

Alfa AF: 0.0261 Hom.: 87

Bravo AF: 0.0199

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs72927040; hg19: chr11-64496745;