11-64727506-ATTTT-A

Variant names:

• chr11-64727506-ATTTT-A
• rs34854951
• NM_001098671.2:c.1772-150_1772-147delAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001098671.2(RASGRP2):​c.1772-150_1772-147delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 237,578 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (127 hom., cov: 0)
  • Exomes 𝑓: 0.076 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AFR (0.124) population. However there is too low homozygotes in high coverage region: (expected more than 343, got 1).
• BP6: Variant 11-64727506-ATTTT-A is Benign according to our data. Variant chr11-64727506-ATTTT-A is described in ClinVar as Benign. ClinVar VariationId is 1293849.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1772-150_1772-147delAAAA		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1859-147_1859-144delAAAA		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1859-150_1859-147delAAAA		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.1772-150_1772-147delAAAA		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1772-150_1772-147delAAAA		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1772-150_1772-147delAAAA		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 3665 AN: 74992 Hom.: 125 Cov.: 0

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.00360

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.000841

Gnomad MID AF: 0.0342

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.0508

GnomAD4 exome AF: 0.0761 AC: 18073 AN: 237578 Hom.: 1 AF XY: 0.0746 AC XY: 9627 AN XY: 128964

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

African (AFR) AF: 0.132 AC: 767 AN: 5830

American (AMR) AF: 0.0785 AC: 871 AN: 11102

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 482 AN: 6320

East Asian (EAS) AF: 0.0681 AC: 902 AN: 13248

South Asian (SAS) AF: 0.0693 AC: 2433 AN: 35120

European-Finnish (FIN) AF: 0.0683 AC: 993 AN: 14534

Middle Eastern (MID) AF: 0.0925 AC: 89 AN: 962

European-Non Finnish (NFE) AF: 0.0761 AC: 10524 AN: 138264

Other (OTH) AF: 0.0830 AC: 1012 AN: 12198

⚠️ 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: 0.0489 AC: 3671 AN: 75002 Hom.: 127 Cov.: 0 AF XY: 0.0492 AC XY: 1693 AN XY: 34390

African (AFR) AF: 0.149 AC: 3288 AN: 22072

American (AMR) AF: 0.0335 AC: 214 AN: 6394

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 7 AN: 1946

East Asian (EAS) AF: 0.00 AC: 0 AN: 2606

South Asian (SAS) AF: 0.00112 AC: 2 AN: 1788

European-Finnish (FIN) AF: 0.000841 AC: 2 AN: 2378

Middle Eastern (MID) AF: 0.0385 AC: 5 AN: 130

European-Non Finnish (NFE) AF: 0.00290 AC: 105 AN: 36222

Other (OTH) AF: 0.0504 AC: 48 AN: 952

Alfa AF: 0.00 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		0.29
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;