11-64729045-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001098671.2(RASGRP2):c.1592-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,591,750 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (82 hom.)
• Consequence: RASGRP2 NM_001098671.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9562
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.18

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 11-64729045-G-T is Benign according to our data. Variant chr11-64729045-G-T is described in ClinVar as [Benign]. Clinvar id is 284960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP2	NM_001098671.2	c.1592-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP2	ENST00000394432.8	c.1592-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001098671.2	P4

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2738 AN: 152186 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00850

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00576 AC: 1260 AN: 218840 Hom.: 36 AF XY: 0.00442 AC XY: 526 AN XY: 119112

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00383

Gnomad ASJ exome AF: 0.00819

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00214

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00373

GnomAD4 exome AF: 0.00262 AC: 3766 AN: 1439446 Hom.: 82 Cov.: 32 AF XY: 0.00245 AC XY: 1755 AN XY: 715430

Gnomad4 AFR exome AF: 0.0619

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.00859

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00243

Gnomad4 FIN exome AF: 0.0000245

Gnomad4 NFE exome AF: 0.000691

Gnomad4 OTH exome AF: 0.00494

GnomAD4 genome AF: 0.0180 AC: 2742 AN: 152304 Hom.: 79 Cov.: 32 AF XY: 0.0172 AC XY: 1282 AN XY: 74474

Gnomad4 AFR AF: 0.0600

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00818 Hom.: 3

Bravo AF: 0.0203

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	This variant is associated with the following publications: (PMID: 27884173, 17576779, 25525159) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.010		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: rs75902820; hg19: chr11-64496517; COSMIC: COSV62451333; COSMIC: COSV62451333;