Genetic Variant VAX2:p.Arg28Cys (chr2-70900703-C-T) – 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_012476.3(VAX2):c.82C>T(p.Arg28Cys) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VAX2
NM_012476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0500

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:

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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=0.25092074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3 link	c.82C>T	p.Arg28Cys	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1	Q9UIW0F1T0K5
VAX2	XM_011532750.4 link	c.82C>T	p.Arg28Cys	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4 link	c.82C>T	p.Arg28Cys	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.82C>T	p.Arg28Cys	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2	Q9UIW0
VAX2	ENST00000432367.6 link	n.-96C>T		upstream_gene_variant		5		ENSP00000405114.2	C9J5E3
ENSG00000296671	ENST00000741094.1 link	n.-234G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1204050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

584160

African (AFR)

AF:

0.00

AC:

AN:

24376

American (AMR)

AF:

0.00

AC:

AN:

13424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17894

East Asian (EAS)

AF:

0.00

AC:

AN:

27252

South Asian (SAS)

AF:

0.00

AC:

AN:

51322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3406

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

984138

Other (OTH)

AF:

0.00

AC:

AN:

48966

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.82C>T (p.R28C) alteration is located in exon 1 (coding exon 1) of the VAX2 gene. This alteration results from a C to T substitution at nucleotide position 82, causing the arginine (R) at amino acid position 28 to be replaced by a cysteine (C). 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

0.10

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.0

PhyloP100

0.050

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Benign

0.038

Sift4G

Uncertain

0.056

Polyphen

0.86

Vest4

0.11

MutPred

0.44

Loss of MoRF binding (P = 6e-04);

MVP

0.95

MPC

0.076

ClinPred

0.34

GERP RS

1.2

PromoterAI

-0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.12

gMVP

0.21

Mutation Taster

=90/10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over