11-64727506-ATTTTTTTTTTTTTT-ATTTTTTTTTTTT

Variant names:

• chr11-64727506-ATT-A
• rs34854951
• NM_001098671.2:c.1772-148_1772-147delAA

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.1772-148_1772-147delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 246,780 control chromosomes in the GnomAD database, including 208 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (7585 hom., cov: 0)
  • Exomes 𝑓: 0.35 (208 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.227
• 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-ATT-A is Benign according to our data. Variant chr11-64727506-ATT-A is described in ClinVar as Benign. ClinVar VariationId is 1286700.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 208 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.1772-148_1772-147delAA		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1859-145_1859-144delAA		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1859-148_1859-147delAA		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.1772-148_1772-147delAA		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1772-148_1772-147delAA		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1772-148_1772-147delAA		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 38426 AN: 76244 Hom.: 7594 Cov.: 0

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.496

GnomAD4 exome AF: 0.348 AC: 85871 AN: 246780 Hom.: 208 AF XY: 0.348 AC XY: 46772 AN XY: 134226

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

African (AFR) AF: 0.236 AC: 1380 AN: 5846

American (AMR) AF: 0.315 AC: 3631 AN: 11524

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 2296 AN: 6542

East Asian (EAS) AF: 0.336 AC: 4579 AN: 13614

South Asian (SAS) AF: 0.351 AC: 12964 AN: 36944

European-Finnish (FIN) AF: 0.346 AC: 5214 AN: 15064

Middle Eastern (MID) AF: 0.346 AC: 340 AN: 984

European-Non Finnish (NFE) AF: 0.355 AC: 51013 AN: 143594

Other (OTH) AF: 0.352 AC: 4454 AN: 12668

⚠️ 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: 0.504 AC: 38417 AN: 76256 Hom.: 7585 Cov.: 0 AF XY: 0.504 AC XY: 17581 AN XY: 34910

African (AFR) AF: 0.304 AC: 6695 AN: 22024

American (AMR) AF: 0.526 AC: 3450 AN: 6554

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 1231 AN: 2002

East Asian (EAS) AF: 0.551 AC: 1479 AN: 2682

South Asian (SAS) AF: 0.695 AC: 1260 AN: 1812

European-Finnish (FIN) AF: 0.645 AC: 1547 AN: 2400

Middle Eastern (MID) AF: 0.692 AC: 90 AN: 130

European-Non Finnish (NFE) AF: 0.589 AC: 21864 AN: 37146

Other (OTH) AF: 0.497 AC: 483 AN: 972

Alfa AF: 0.378 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		-0.23
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;