Genetic Variant RASGRP2:c.1772-153_1772-147delAAAAAAA (chr11-64727506-ATTTTTTT-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001098671.2(RASGRP2):c.1772-153_1772-147delAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00091 in 248,236 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: 0.00091 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASGRP2
NM_001098671.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.288

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 0 ACMG points.

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.1772-153_1772-147delAAAAAAA	intron	N/A	NP_001092141.1	Q7LDG7-1
RASGRP2	NM_001440703.1		c.1859-150_1859-144delAAAAAAA	intron	N/A	NP_001427632.1
RASGRP2	NM_001440704.1		c.1859-153_1859-147delAAAAAAA	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.1772-153_1772-147delAAAAAAA	intron	N/A	ENSP00000377953.3	Q7LDG7-1
RASGRP2	ENST00000354024.7	TSL:1	c.1772-153_1772-147delAAAAAAA	intron	N/A	ENSP00000338864.3	Q7LDG7-1
RASGRP2	ENST00000377497.7	TSL:1	c.1772-153_1772-147delAAAAAAA	intron	N/A	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

74966

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:

0.000910

AC:

226

AN:

248236

Hom.:

AF XY:

0.000844

AC XY:

114

AN XY:

134996

show subpopulations

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

African (AFR)

AF:

0.00199

AC:

AN:

6020

American (AMR)

AF:

0.00112

AC:

AN:

11624

Ashkenazi Jewish (ASJ)

AF:

0.000456

AC:

AN:

6576

East Asian (EAS)

AF:

0.00102

AC:

AN:

13680

South Asian (SAS)

AF:

0.000403

AC:

AN:

37186

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

15112

Middle Eastern (MID)

AF:

0.00504

AC:

AN:

992

European-Non Finnish (NFE)

AF:

0.000936

AC:

135

AN:

144306

Other (OTH)

AF:

0.000942

AC:

AN:

12740

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.254

Heterozygous variant carriers

111

139

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:

74966

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:

36236

Other (OTH)

AF:

0.00

AC:

AN:

946

Alfa

AF:

0.00

Hom.:

334

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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11-64727506-ATTTTTTTTTTTTTT-ATTTTTTT

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