11-64728885-G-T

Variant names:

• chr11-64728885-G-T
• rs2230414
• NM_001098671.2:c.1749C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001098671.2(RASGRP2):​c.1749C>A​(p.Gly583Gly) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G583G) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: -0.770
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 18

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• osteopetrosis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098671.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	NM_001098671.2	MANE Select	c.1749C>A	p.Gly583Gly	synonymous	Exon 15 of 17	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1836C>A	p.Gly612Gly	synonymous	Exon 16 of 18	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1836C>A	p.Gly612Gly	synonymous	Exon 16 of 18	NP_001427633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1749C>A	p.Gly583Gly	synonymous	Exon 15 of 17	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1749C>A	p.Gly583Gly	synonymous	Exon 15 of 17	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1749C>A	p.Gly583Gly	synonymous	Exon 15 of 17	ENSP00000366717.3	Q7LDG7-1

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

GnomAD2 exomes AF: 0.155 AC: 38279 AN: 247532 AF XY: 0.149

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 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

African (AFR) AF: 0.110 AC: 3679 AN: 33470

American (AMR) AF: 0.299 AC: 13342 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3771 AN: 26112

East Asian (EAS) AF: 0.370 AC: 14672 AN: 39670

South Asian (SAS) AF: 0.160 AC: 13805 AN: 86218

European-Finnish (FIN) AF: 0.111 AC: 5787 AN: 51970

Middle Eastern (MID) AF: 0.108 AC: 615 AN: 5706

European-Non Finnish (NFE) AF: 0.0933 AC: 103663 AN: 1111408

Other (OTH) AF: 0.123 AC: 7437 AN: 60334

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

African (AFR) AF: 0.111 AC: 4607 AN: 41558

American (AMR) AF: 0.248 AC: 3786 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3468

East Asian (EAS) AF: 0.348 AC: 1800 AN: 5166

South Asian (SAS) AF: 0.170 AC: 821 AN: 4820

European-Finnish (FIN) AF: 0.111 AC: 1174 AN: 10600

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0992 AC: 6745 AN: 68012

Other (OTH) AF: 0.140 AC: 297 AN: 2116

Alfa AF: 0.112 Hom.: 3498

Bravo AF: 0.141

Asia WGS AF: 0.259 AC: 901 AN: 3478

EpiCase AF: 0.0990

EpiControl AF: 0.100

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.4
DANN	Benign	0.67
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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