NM_001098671.2:c.1772-148_1772-147dupAA

Variant names:

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

Variant summary

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

The NM_001098671.2(RASGRP2):​c.1772-148_1772-147dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 323,426 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 0.00044 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00056 (0 hom.)
• 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 afr. GnomAd4 allele frequency = 0.00044 (33/74972) while in subpopulation AFR AF = 0.00141 (31/22050). AF 95% confidence interval is 0.00102. There are 0 homozygotes in GnomAd4. There are 19 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.1772-148_1772-147dupAA		intron	N/A	NP_001092141.1	Q7LDG7-1
	RASGRP2	NM_001440703.1		c.1859-145_1859-144dupAA		intron	N/A	NP_001427632.1
	RASGRP2	NM_001440704.1		c.1859-148_1859-147dupAA		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_1772-146insAA		intron	N/A	ENSP00000377953.3	Q7LDG7-1
	RASGRP2	ENST00000354024.7	TSL:1	c.1772-147_1772-146insAA		intron	N/A	ENSP00000338864.3	Q7LDG7-1
	RASGRP2	ENST00000377497.7	TSL:1	c.1772-147_1772-146insAA		intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 33 AN: 74958 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000276

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000559 AC: 139 AN: 248454 Hom.: 0 AF XY: 0.000496 AC XY: 67 AN XY: 135096

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

African (AFR) AF: 0.00432 AC: 26 AN: 6018

American (AMR) AF: 0.000860 AC: 10 AN: 11624

Ashkenazi Jewish (ASJ) AF: 0.000457 AC: 3 AN: 6568

East Asian (EAS) AF: 0.000657 AC: 9 AN: 13706

South Asian (SAS) AF: 0.000295 AC: 11 AN: 37258

European-Finnish (FIN) AF: 0.000264 AC: 4 AN: 15126

Middle Eastern (MID) AF: 0.00202 AC: 2 AN: 988

European-Non Finnish (NFE) AF: 0.000457 AC: 66 AN: 144422

Other (OTH) AF: 0.000628 AC: 8 AN: 12744

⚠️ 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: 0.000440 AC: 33 AN: 74972 Hom.: 0 Cov.: 0 AF XY: 0.000553 AC XY: 19 AN XY: 34368

African (AFR) AF: 0.00141 AC: 31 AN: 22050

American (AMR) AF: 0.000157 AC: 1 AN: 6382

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000276 AC: 1 AN: 36224

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;