Genetic Variant VAX2:p.Pro68Ser (chr2-70900823-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012476.3(VAX2):c.202C>T(p.Pro68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 1,329,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.129

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051104337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 1 of 3	ENST00000234392.3	NP_036608.1	Q9UIW0F1T0K5
VAX2	XM_011532750.4 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 1 of 4		XP_011531052.1
VAX2	XM_011532751.4 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 1 of 4		XP_011531053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAX2	ENST00000234392.3 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 1 of 3	1	NM_012476.3	ENSP00000234392.2		Q9UIW0
VAX2	ENST00000432367.6 link	n.25C>T		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000405114.2		C9J5E3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

89952

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00000226

AC:

AN:

1329230

Hom.:

Cov.:

AF XY:

0.00000306

AC XY:

AN XY:

654288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27734

American (AMR)

AF:

0.00

AC:

AN:

28842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23210

East Asian (EAS)

AF:

0.00

AC:

AN:

30460

South Asian (SAS)

AF:

0.00

AC:

AN:

71996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3900

European-Non Finnish (NFE)

AF:

0.00000286

AC:

AN:

1048334

Other (OTH)

AF:

0.00

AC:

AN:

54946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.202C>T (p.P68S) 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 202, causing the proline (P) at amino acid position 68 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

0.079

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.051

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.0

PhyloP100

-0.13

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.65

REVEL

Benign

0.14

Sift

Benign

0.53

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.051

MutPred

0.22

Gain of glycosylation at P68 (P = 0.0088);

MVP

0.87

MPC

0.041

ClinPred

0.063

GERP RS

1.9

PromoterAI

-0.0076

Neutral

(source)

Varity_R

0.048

gMVP

0.14

Mutation Taster

=93/7

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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2-70900823-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over