11-64727506-ATTTTTTTTTTTTTT-ATTTTTTTTTTTTT

Variant names:

• chr11-64727506-AT-A
• rs34854951
• NM_001098671.2:c.1772-147delA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001098671.2(RASGRP2):​c.1772-147delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 240,620 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (660 hom., cov: 0)
  • Exomes 𝑓: 0.19 (16 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 11-64727506-AT-A is Benign according to our data. Variant chr11-64727506-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1226530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

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.1772-147delA		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1859-144delA		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1859-147delA		intron	N/A	NP_001427633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1772-147delA		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1772-147delA		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1772-147delA		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 14680 AN: 75214 Hom.: 662 Cov.: 0

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.160

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.191 AC: 45904 AN: 240620 Hom.: 16 AF XY: 0.191 AC XY: 24993 AN XY: 130788

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.164 AC: 952 AN: 5816

American (AMR) AF: 0.212 AC: 2375 AN: 11214

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 1163 AN: 6396

East Asian (EAS) AF: 0.233 AC: 3111 AN: 13380

South Asian (SAS) AF: 0.179 AC: 6381 AN: 35622

European-Finnish (FIN) AF: 0.194 AC: 2869 AN: 14810

Middle Eastern (MID) AF: 0.173 AC: 166 AN: 958

European-Non Finnish (NFE) AF: 0.190 AC: 26557 AN: 140026

Other (OTH) AF: 0.188 AC: 2330 AN: 12398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.195 AC: 14681 AN: 75228 Hom.: 660 Cov.: 0 AF XY: 0.192 AC XY: 6627 AN XY: 34470

African (AFR) AF: 0.143 AC: 3148 AN: 22040

American (AMR) AF: 0.270 AC: 1729 AN: 6414

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 353 AN: 1948

East Asian (EAS) AF: 0.302 AC: 787 AN: 2608

South Asian (SAS) AF: 0.184 AC: 331 AN: 1796

European-Finnish (FIN) AF: 0.211 AC: 505 AN: 2396

Middle Eastern (MID) AF: 0.148 AC: 19 AN: 128

European-Non Finnish (NFE) AF: 0.207 AC: 7543 AN: 36428

Other (OTH) AF: 0.214 AC: 204 AN: 954

Alfa AF: 0.119 Hom.: 334

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.0
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: rs34854951; hg19: chr11-64494978;