9-133771997-T-C

Variant names:

• chr9-133771997-T-C
• NM_001134398.2:c.2185A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134398.2(VAV2):​c.2185A>G​(p.Ile729Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VAV2 NM_001134398.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 0 publications found

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]

ACMG classification

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=0.18620875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV2	NM_001134398.2	c.2185A>G	p.Ile729Val	missense_variant	Exon 26 of 30	ENST00000371850.8	NP_001127870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV2	ENST00000371850.8	c.2185A>G	p.Ile729Val	missense_variant	Exon 26 of 30	1	NM_001134398.2	ENSP00000360916.3
VAV2	ENST00000406606.7	c.2155A>G	p.Ile719Val	missense_variant	Exon 24 of 27	1		ENSP00000385362.3
VAV2	ENST00000371851.1	c.2155A>G	p.Ile719Val	missense_variant	Exon 24 of 28	5		ENSP00000360917.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2185A>G (p.I729V) 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 2185, causing the isoleucine (I) at amino acid position 729 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.63	.;N;.
PhyloP100		3.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.098	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.24
MutPred		0.56		.;Loss of sheet (P = 0.0817);.;
MVP		0.54
MPC		0.26
ClinPred		0.76	D
GERP RS		1.6
Varity_R		0.040
gMVP		0.28
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

hg19: chr9-136637119;