NM_001098671.2:c.1772-155_1772-147dupAAAAAAAAA

Variant names:

• chr11-64727506-A-ATTTTTTTTT
• rs34854951
• NM_001098671.2:c.1772-155_1772-147dupAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001098671.2(RASGRP2):​c.1772-155_1772-147dupAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGRP2 NM_001098671.2 intron
• Clinical Significance: Not reported in ClinVar
• 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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000253 (19/74972) while in subpopulation SAS AF = 0.0101 (18/1780). AF 95% confidence interval is 0.00654. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.1772-155_1772-147dupAAAAAAAAA		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1859-152_1859-144dupAAAAAAAAA		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1859-155_1859-147dupAAAAAAAAA		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.1772-147_1772-146insAAAAAAAAA		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1772-147_1772-146insAAAAAAAAA		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1772-147_1772-146insAAAAAAAAA		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 18 AN: 74958 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00950

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000276

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000446 AC: 111 AN: 248804 Hom.: 0 AF XY: 0.000665 AC XY: 90 AN XY: 135276

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

African (AFR) AF: 0.00 AC: 0 AN: 6042

American (AMR) AF: 0.00 AC: 0 AN: 11646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6584

East Asian (EAS) AF: 0.00 AC: 0 AN: 13724

South Asian (SAS) AF: 0.00295 AC: 110 AN: 37250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 144656

Other (OTH) AF: 0.0000784 AC: 1 AN: 12762

⚠️ 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 AF: 0.000253 AC: 19 AN: 74972 Hom.: 0 Cov.: 0 AF XY: 0.000466 AC XY: 16 AN XY: 34364

African (AFR) AF: 0.00 AC: 0 AN: 22054

American (AMR) AF: 0.00 AC: 0 AN: 6382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1948

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

South Asian (SAS) AF: 0.0101 AC: 18 AN: 1780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2380

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

European-Non Finnish (NFE) AF: 0.0000276 AC: 1 AN: 36226

Other (OTH) AF: 0.00 AC: 0 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		-1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34854951; hg19: chr11-64494978;