14-74239648-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_182894.3(VSX2):c.87C>A(p.Cys29Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000214 in 1,398,652 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
VSX2
NM_182894.3 stop_gained
NM_182894.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.32
Genes affected
VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-74239648-C-A is Pathogenic according to our data. Variant chr14-74239648-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1411209.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VSX2 | NM_182894.3 | c.87C>A | p.Cys29Ter | stop_gained | 1/5 | ENST00000261980.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VSX2 | ENST00000261980.3 | c.87C>A | p.Cys29Ter | stop_gained | 1/5 | 1 | NM_182894.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000651 AC: 1AN: 153592Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 81424
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GnomAD4 exome AF: 0.00000214 AC: 3AN: 1398652Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1AN XY: 689818
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GnomAD4 genome Cov.: 33
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33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Isolated microphthalmia 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2021 | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with VSX2-related conditions. This sequence change creates a premature translational stop signal (p.Cys29*) in the VSX2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VSX2 are known to be pathogenic (PMID: 20414678). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
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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