Variant 2-70900676-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012476.3(VAX2):c.55G>A(p.Gly19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,292,512 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00073 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.18

Variant links:

Genes affected

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

VAX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0076780617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VAX2	NM_012476.3 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	1/3	ENST00000234392.3	NP_036608.1
VAX2	XM_011532750.4 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	1/4		XP_011531052.1
VAX2	XM_011532751.4 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	1/4		XP_011531053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAX2	ENST00000234392.3 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	1/3	1	NM_012476.3	ENSP00000234392	P1

Frequencies

GnomAD3 genomes

AF:

0.000730

AC:

111

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000228

AC:

AN:

4380

Hom.:

AF XY:

0.00

AC XY:

AN XY:

2822

show subpopulations

Gnomad AFR exome

AF:

0.0135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

130

AN:

1140258

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

546898

show subpopulations

Gnomad4 AFR exome

AF:

0.00249

Gnomad4 AMR exome

AF:

0.000338

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000373

Gnomad4 SAS exome

AF:

0.0000534

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000420

Gnomad4 OTH exome

AF:

0.000412

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152254

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000712

Hom.:

Bravo

AF:

0.000793

ExAC

AF:

0.0000571

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.55G>A (p.G19S) alteration is located in exon 1 (coding exon 1) of the VAX2 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the glycine (G) at amino acid position 19 to be replaced by a serine (S). 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

0.092

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.72

REVEL

Benign

0.17

Sift

Benign

0.16

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.14

MutPred

0.27

Gain of phosphorylation at G19 (P = 0.0051);

MVP

0.95

MPC

0.041

ClinPred

0.078

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.073

gMVP

0.11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over