chr2-70921221-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_012476.3(VAX2):ā€‹c.371G>Cā€‹(p.Cys124Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000042 ( 0 hom. )

Consequence

VAX2
NM_012476.3 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.45
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VAX2NM_012476.3 linkuse as main transcriptc.371G>C p.Cys124Ser missense_variant 2/3 ENST00000234392.3
VAX2XM_011532750.4 linkuse as main transcriptc.371G>C p.Cys124Ser missense_variant 2/4
VAX2XM_011532751.4 linkuse as main transcriptc.371G>C p.Cys124Ser missense_variant 2/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VAX2ENST00000234392.3 linkuse as main transcriptc.371G>C p.Cys124Ser missense_variant 2/31 NM_012476.3 P1
VAX2ENST00000432367.6 linkuse as main transcriptc.197G>C p.Cys66Ser missense_variant, NMD_transcript_variant 2/155
VAX2ENST00000646783.1 linkuse as main transcriptc.17G>C p.Cys6Ser missense_variant, NMD_transcript_variant 1/13

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
250150
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135382
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:
0.0000417
AC:
61
AN:
1461402
Hom.:
0
Cov.:
30
AF XY:
0.0000330
AC XY:
24
AN XY:
727006
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:
0.0000531
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 09, 2022The c.371G>C (p.C124S) alteration is located in exon 2 (coding exon 2) of the VAX2 gene. This alteration results from a G to C substitution at nucleotide position 371, causing the cysteine (C) at amino acid position 124 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisOct 23, 2023The VAX2 c.371G>C (p.Cys124Ser) variant, to our knowledge, has not been reported in the medical literature and is only observed on 2/250,150 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant changes a nonpolar cysteine to a polar serine, the variant resides within the homeobox region at the end of a helix, and computational predictors indicate that the variant is damaging, evidence that correlates with impact to VAX2 function. Due to limited information, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
-0.48
N
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.2
D
REVEL
Pathogenic
0.65
Sift
Benign
0.24
T
Sift4G
Benign
0.52
T
Polyphen
0.35
B
Vest4
0.82
MutPred
0.42
Gain of disorder (P = 0.0067);
MVP
0.99
MPC
0.13
ClinPred
0.62
D
GERP RS
5.4
Varity_R
0.50
gMVP
0.45

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: rs781991079; hg19: chr2-71148351; API