chr2-70921221-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_012476.3(VAX2):āc.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
NM_012476.3 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 9.45
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]
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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 |
---|---|---|---|---|---|---|---|
VAX2 | NM_012476.3 | c.371G>C | p.Cys124Ser | missense_variant | 2/3 | ENST00000234392.3 | |
VAX2 | XM_011532750.4 | c.371G>C | p.Cys124Ser | missense_variant | 2/4 | ||
VAX2 | XM_011532751.4 | c.371G>C | p.Cys124Ser | missense_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VAX2 | ENST00000234392.3 | c.371G>C | p.Cys124Ser | missense_variant | 2/3 | 1 | NM_012476.3 | P1 | |
VAX2 | ENST00000432367.6 | c.197G>C | p.Cys66Ser | missense_variant, NMD_transcript_variant | 2/15 | 5 | |||
VAX2 | ENST00000646783.1 | c.17G>C | p.Cys6Ser | missense_variant, NMD_transcript_variant | 1/13 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250150Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135382
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GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461402Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 727006
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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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 submitter | clinical testing | Ambry Genetics | Nov 09, 2022 | The 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 submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 23, 2023 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of disorder (P = 0.0067);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at