11-64727506-ATTTTTTTTTTTTTT-ATTTTTTTTTTT

Variant names:

• chr11-64727506-ATTT-A
• rs34854951
• NM_001098671.2:c.1772-149_1772-147delAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001098671.2(RASGRP2):​c.1772-149_1772-147delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 240,182 control chromosomes in the GnomAD database, including 7 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0059 (2 hom., cov: 0)
  • Exomes 𝑓: 0.20 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.288
• 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 -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 7 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.1772-149_1772-147delAAA		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1859-146_1859-144delAAA		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1859-149_1859-147delAAA		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.1772-149_1772-147delAAA		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1772-149_1772-147delAAA		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1772-149_1772-147delAAA		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 445 AN: 74962 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.0116

Gnomad AMR AF: 0.00972

Gnomad ASJ AF: 0.00154

Gnomad EAS AF: 0.00306

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.00714

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00646

Gnomad OTH AF: 0.00846

GnomAD4 exome AF: 0.204 AC: 48945 AN: 240182 Hom.: 7 AF XY: 0.203 AC XY: 26538 AN XY: 130468

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

African (AFR) AF: 0.130 AC: 758 AN: 5836

American (AMR) AF: 0.189 AC: 2103 AN: 11124

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 1367 AN: 6418

East Asian (EAS) AF: 0.191 AC: 2546 AN: 13338

South Asian (SAS) AF: 0.210 AC: 7448 AN: 35510

European-Finnish (FIN) AF: 0.200 AC: 2947 AN: 14714

Middle Eastern (MID) AF: 0.198 AC: 190 AN: 960

European-Non Finnish (NFE) AF: 0.208 AC: 29153 AN: 139912

Other (OTH) AF: 0.197 AC: 2433 AN: 12370

⚠️ 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: 0.00595 AC: 446 AN: 74976 Hom.: 2 Cov.: 0 AF XY: 0.00640 AC XY: 220 AN XY: 34358

African (AFR) AF: 0.00463 AC: 102 AN: 22046

American (AMR) AF: 0.00971 AC: 62 AN: 6384

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 3 AN: 1946

East Asian (EAS) AF: 0.00307 AC: 8 AN: 2606

South Asian (SAS) AF: 0.00336 AC: 6 AN: 1788

European-Finnish (FIN) AF: 0.00714 AC: 17 AN: 2382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 128

European-Non Finnish (NFE) AF: 0.00646 AC: 234 AN: 36226

Other (OTH) AF: 0.00839 AC: 8 AN: 954

Alfa AF: 0.00 Hom.: 334

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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;