11-64727354-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001098671.2(RASGRP2):c.1778G>A(p.Arg593His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R593C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00081 ( 0 hom. )

Consequence

RASGRP2
NM_001098671.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.894

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040214896).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00046 (70/152228) while in subpopulation NFE AF = 0.000912 (62/68004). AF 95% confidence interval is 0.000729. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1778G>A	p.Arg593His	missense	Exon 16 of 17	NP_001092141.1	Q7LDG7-1
RASGRP2	NM_001440703.1		c.1868G>A	p.Arg623His	missense	Exon 17 of 18	NP_001427632.1
RASGRP2	NM_001440704.1		c.1865G>A	p.Arg622His	missense	Exon 17 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.1778G>A	p.Arg593His	missense	Exon 16 of 17	ENSP00000377953.3	Q7LDG7-1
RASGRP2	ENST00000354024.7	TSL:1	c.1778G>A	p.Arg593His	missense	Exon 16 of 17	ENSP00000338864.3	Q7LDG7-1
RASGRP2	ENST00000377497.7	TSL:1	c.1778G>A	p.Arg593His	missense	Exon 16 of 17	ENSP00000366717.3	Q7LDG7-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000912

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000314

AC:

AN:

251380

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000642

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000811

AC:

1186

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

546

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00100

AC:

1114

AN:

1111868

Other (OTH)

AF:

0.00116

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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

AF:

0.000460

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41534

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000912

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000501

Hom.:

Bravo

AF:

0.000453

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.061

Eigen_PC

Benign

0.046

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.029

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.34

PhyloP100

0.89

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

REVEL

Benign

0.069

Sift

Uncertain

0.012

Sift4G

Benign

0.14

Polyphen

0.90

Vest4

0.29

MVP

0.29

MPC

0.76

ClinPred

0.062

GERP RS

3.6

Varity_R

0.11

gMVP

0.41

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over