Genetic Variant VAV2:p.Lys725Arg (chr9-133772008-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001134398.2(VAV2):c.2174A>G(p.Lys725Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000098 in 102,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000098 ( 0 hom., cov: 31)

Consequence

VAV2
NM_001134398.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49

Publications

0 publications found

Variant links:

Genes affected

VAV2 (HGNC:12658): (vav guanine nucleotide exchange factor 2) VAV2 is the second member of the VAV guanine nucleotide exchange factor family of oncogenes. Unlike VAV1, which is expressed exclusively in hematopoietic cells, VAV2 transcripts were found in most tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

VAV2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23112091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV2	NM_001134398.2 link	c.2174A>G	p.Lys725Arg	missense_variant	Exon 26 of 30	ENST00000371850.8	NP_001127870.1	P52735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VAV2	ENST00000371850.8 link	c.2174A>G	p.Lys725Arg	missense_variant	Exon 26 of 30	1	NM_001134398.2	ENSP00000360916.3	P52735-1
VAV2	ENST00000406606.7 link	c.2144A>G	p.Lys715Arg	missense_variant	Exon 24 of 27	1		ENSP00000385362.3	P52735-3
VAV2	ENST00000371851.1 link	c.2144A>G	p.Lys715Arg	missense_variant	Exon 24 of 28	5		ENSP00000360917.1	P52735-2

Frequencies

GnomAD3 genomes

AF:

0.00000980

AC:

AN:

102044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

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

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248380

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000980

AC:

AN:

102044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29350

American (AMR)

AF:

0.00

AC:

AN:

10442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2364

East Asian (EAS)

AF:

0.000201

AC:

AN:

4970

South Asian (SAS)

AF:

0.00

AC:

AN:

3136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42612

Other (OTH)

AF:

0.00

AC:

AN:

1384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2174A>G (p.K725R) alteration is located in exon 26 (coding exon 26) of the VAV2 gene. This alteration results from a A to G substitution at nucleotide position 2174, causing the lysine (K) at amino acid position 725 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;T;.

Eigen

Benign

-0.073

Eigen_PC

Benign

0.038

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

.;L;.

PhyloP100

7.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.70

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.60

T;T;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.030

B;D;B

Vest4

0.60

MutPred

0.45

.;Loss of ubiquitination at K725 (P = 0.0199);.;

MVP

0.60

MPC

0.34

ClinPred

0.36

GERP RS

4.1

Varity_R

0.24

gMVP

0.45

Mutation Taster

=50/50

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over