Genetic Variant NM_001098671.2:c.1627C>G (chr11-64729007-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001098671.2(RASGRP2):c.1627C>G(p.Arg543Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R543C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RASGRP2
NM_001098671.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.33

Publications

3 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4231934).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP2	NM_001098671.2	MANE Select	c.1627C>G	p.Arg543Gly	missense	Exon 15 of 17	NP_001092141.1	Q7LDG7-1
RASGRP2	NM_001440703.1		c.1714C>G	p.Arg572Gly	missense	Exon 16 of 18	NP_001427632.1
RASGRP2	NM_001440704.1		c.1714C>G	p.Arg572Gly	missense	Exon 16 of 18	NP_001427633.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP2	ENST00000394432.8	TSL:1 MANE Select	c.1627C>G	p.Arg543Gly	missense	Exon 15 of 17	ENSP00000377953.3	Q7LDG7-1
RASGRP2	ENST00000354024.7	TSL:1	c.1627C>G	p.Arg543Gly	missense	Exon 15 of 17	ENSP00000338864.3	Q7LDG7-1
RASGRP2	ENST00000377497.7	TSL:1	c.1627C>G	p.Arg543Gly	missense	Exon 15 of 17	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000421

AC:

AN:

237762

AF XY:

0.00000773

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Benign

0.065

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.42

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.4

PhyloP100

8.3

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.47

Sift

Benign

0.10

Sift4G

Benign

0.12

Polyphen

0.058

Vest4

0.49

MVP

0.58

MPC

0.62

ClinPred

0.95

GERP RS

4.6

Varity_R

0.19

gMVP

0.59

Mutation Taster

=74/26

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over