Genetic Variant VAX2:p.Gly19Ser (chr2-70900676-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 14/22 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

Publications

0 publications found

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:

ENSG00000296671 (HGNC:):

ENSG00000296671 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3 link	c.55G>A	p.Gly19Ser	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1	Q9UIW0F1T0K5
VAX2	XM_011532750.4 link	c.55G>A	p.Gly19Ser	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4 link	c.55G>A	p.Gly19Ser	missense_variant	Exon 1 of 4		XP_011531053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VAX2	ENST00000234392.3 link	c.55G>A	p.Gly19Ser	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2	Q9UIW0
VAX2	ENST00000432367.6 link	n.-123G>A		upstream_gene_variant		5		ENSP00000405114.2	C9J5E3
ENSG00000296671	ENST00000741094.1 link	n.-207C>T		upstream_gene_variant

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

GnomAD2 exomes

AF:

0.000228

AC:

AN:

4380

AF XY:

0.00

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 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

African (AFR)

AF:

0.00249

AC:

AN:

23334

American (AMR)

AF:

0.000338

AC:

AN:

8888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15482

East Asian (EAS)

AF:

0.0000373

AC:

AN:

26814

South Asian (SAS)

AF:

0.0000534

AC:

AN:

37472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27584

Middle Eastern (MID)

AF:

0.00224

AC:

AN:

3126

European-Non Finnish (NFE)

AF:

0.0000420

AC:

AN:

951426

Other (OTH)

AF:

0.000412

AC:

AN:

46132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152254

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41570

American (AMR)

AF:

0.000784

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67986

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Sep 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

2.2

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

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.073

gMVP

0.11

Mutation Taster

=92/8

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.

2-70900676-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over