Genetic Variant RASGRP2:c.1772-150_1772-147dupAAAA (chr11-64727506-A-ATTTT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001098671.2(RASGRP2):c.1772-150_1772-147dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 248,846 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 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASGRP2
NM_001098671.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.03

Publications

0 publications found

Variant links:

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

RASGRP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RASGRP2	NM_001098671.2	MANE Select	c.1772-150_1772-147dupAAAA	intron	N/A	NP_001092141.1	Q7LDG7-1
RASGRP2	NM_001440703.1		c.1859-147_1859-144dupAAAA	intron	N/A	NP_001427632.1
RASGRP2	NM_001440704.1		c.1859-150_1859-147dupAAAA	intron	N/A	NP_001427633.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1772-147_1772-146insAAAA	intron	N/A	ENSP00000377953.3	Q7LDG7-1
RASGRP2	ENST00000354024.7	TSL:1	c.1772-147_1772-146insAAAA	intron	N/A	ENSP00000338864.3	Q7LDG7-1
RASGRP2	ENST00000377497.7	TSL:1	c.1772-147_1772-146insAAAA	intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

74964

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000161

AC:

AN:

248846

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135316

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

6042

American (AMR)

AF:

0.00

AC:

AN:

11644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6584

East Asian (EAS)

AF:

0.00

AC:

AN:

13724

South Asian (SAS)

AF:

0.0000268

AC:

AN:

37296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

992

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

144652

Other (OTH)

AF:

0.0000783

AC:

AN:

12764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000108036), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.288

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

74964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34340

African (AFR)

AF:

0.00

AC:

AN:

22008

American (AMR)

AF:

0.00

AC:

AN:

6376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1948

East Asian (EAS)

AF:

0.00

AC:

AN:

2616

South Asian (SAS)

AF:

0.00

AC:

AN:

1798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

144

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

36234

Other (OTH)

AF:

0.00

AC:

AN:

946

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

Publications

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11-64727506-ATTTTTTTTTTTTTT-ATTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over