11-64727506-ATTTTTTTTTTTTTT-ATTTTTTTTTTTTTTT

Variant names:

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

Variant summary

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

The NM_001098671.2(RASGRP2):​c.1772-147dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 247,574 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0098 (10 hom., cov: 0)
  • Exomes 𝑓: 0.0046 (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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AFR (0.028) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

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

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 735 AN: 74936 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00345

Gnomad ASJ AF: 0.00411

Gnomad EAS AF: 0.000383

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.00530

GnomAD4 exome AF: 0.00459 AC: 1137 AN: 247574 Hom.: 0 AF XY: 0.00440 AC XY: 592 AN XY: 134624

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

African (AFR) AF: 0.0317 AC: 189 AN: 5956

American (AMR) AF: 0.00665 AC: 77 AN: 11578

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 17 AN: 6546

East Asian (EAS) AF: 0.00549 AC: 75 AN: 13660

South Asian (SAS) AF: 0.00269 AC: 100 AN: 37122

European-Finnish (FIN) AF: 0.00384 AC: 58 AN: 15086

Middle Eastern (MID) AF: 0.00506 AC: 5 AN: 988

European-Non Finnish (NFE) AF: 0.00383 AC: 552 AN: 143938

Other (OTH) AF: 0.00504 AC: 64 AN: 12700

⚠️ 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: 0.00979 AC: 734 AN: 74950 Hom.: 10 Cov.: 0 AF XY: 0.00998 AC XY: 343 AN XY: 34358

African (AFR) AF: 0.0310 AC: 684 AN: 22042

American (AMR) AF: 0.00345 AC: 22 AN: 6380

Ashkenazi Jewish (ASJ) AF: 0.00411 AC: 8 AN: 1948

East Asian (EAS) AF: 0.000384 AC: 1 AN: 2604

South Asian (SAS) AF: 0.00 AC: 0 AN: 1788

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: 0.000387 AC: 14 AN: 36216

Other (OTH) AF: 0.00525 AC: 5 AN: 952

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

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;