rs147799977

Variant names:

• chr9-133776055-C-T
• rs147799977
• NM_001134398.2:c.1991G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001134398.2(VAV2):​c.1991G>A​(p.Arg664Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,613,044 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R664W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: VAV2 NM_001134398.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08493456).
• BS2: High AC in GnomAd4 at 125 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134398.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV2	NM_001134398.2	MANE Select	c.1991G>A	p.Arg664Gln	missense	Exon 24 of 30	NP_001127870.1	P52735-1
	VAV2	NM_001411028.1		c.1961G>A	p.Arg654Gln	missense	Exon 22 of 28	NP_001397957.1	P52735-2
	VAV2	NM_003371.4		c.1961G>A	p.Arg654Gln	missense	Exon 22 of 27	NP_003362.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV2	ENST00000371850.8	TSL:1 MANE Select	c.1991G>A	p.Arg664Gln	missense	Exon 24 of 30	ENSP00000360916.3	P52735-1
	VAV2	ENST00000406606.7	TSL:1	c.1961G>A	p.Arg654Gln	missense	Exon 22 of 27	ENSP00000385362.3	P52735-3
	VAV2	ENST00000876887.1		c.2201G>A	p.Arg734Gln	missense	Exon 22 of 27	ENSP00000546946.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152238 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000612 AC: 153 AN: 250168 AF XY: 0.000657

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000947

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1460688 Hom.: 4 Cov.: 30 AF XY: 0.00113 AC XY: 824 AN XY: 726620

African (AFR) AF: 0.000209 AC: 7 AN: 33464

American (AMR) AF: 0.000134 AC: 6 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86156

European-Finnish (FIN) AF: 0.000227 AC: 12 AN: 52896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00141 AC: 1563 AN: 1111640

Other (OTH) AF: 0.000613 AC: 37 AN: 60344

GnomAD4 genome AF: 0.000820 AC: 125 AN: 152356 Hom.: 0 Cov.: 34 AF XY: 0.000577 AC XY: 43 AN XY: 74504

African (AFR) AF: 0.000361 AC: 15 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000946 Hom.: 0

Bravo AF: 0.000752

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.000491

EpiControl AF: 0.000831

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.047
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.14
Sift	Benign	0.36	T
Sift4G	Uncertain	0.039	D
Polyphen		0.35	B
Vest4		0.62
MVP		0.69
MPC		0.68
ClinPred		0.047	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.51
Mutation Taster		=70/30	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

dbSNP: rs147799977; hg19: chr9-136641177;