chr2-70932856-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_012476.3(VAX2):​c.525G>T​(p.Glu175Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3541693).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VAX2NM_012476.3 linkuse as main transcriptc.525G>T p.Glu175Asp missense_variant 3/3 ENST00000234392.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VAX2ENST00000234392.3 linkuse as main transcriptc.525G>T p.Glu175Asp missense_variant 3/31 NM_012476.3 P1
VAX2ENST00000432367.6 linkuse as main transcriptc.*45+8518G>T intron_variant, NMD_transcript_variant 5
VAX2ENST00000646783.1 linkuse as main transcriptc.80-6562G>T intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151890
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000798
AC:
2
AN:
250754
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135612
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1461520
Hom.:
0
Cov.:
32
AF XY:
0.0000358
AC XY:
26
AN XY:
727064
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000378
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151890
Hom.:
0
Cov.:
29
AF XY:
0.0000270
AC XY:
2
AN XY:
74164
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsDec 06, 2023The c.525G>T (p.E175D) alteration is located in exon 3 (coding exon 3) of the VAX2 gene. This alteration results from a G to T substitution at nucleotide position 525, causing the glutamic acid (E) at amino acid position 175 to be replaced by an aspartic acid (D). 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
0.25
BayesDel_addAF
Benign
-0.0029
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T
Eigen
Benign
0.18
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.72
T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.35
T
MetaSVM
Uncertain
0.040
D
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.31
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.044
D
Polyphen
0.90
P
Vest4
0.28
MutPred
0.13
Loss of glycosylation at S174 (P = 0.1809);
MVP
0.96
MPC
0.11
ClinPred
0.76
D
GERP RS
4.1
Varity_R
0.25
gMVP
0.29

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.

Other links and lift over

dbSNP: rs782501912; hg19: chr2-71159986; COSMIC: COSV52266418; COSMIC: COSV52266418; API