rs142233726
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_014000.3(VCL):c.787A>T(p.Thr263Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. T263T) has been classified as Likely benign.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.787A>T | p.Thr263Ser | missense_variant | 7/22 | ENST00000211998.10 | |
VCL | NM_003373.4 | c.787A>T | p.Thr263Ser | missense_variant | 7/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.787A>T | p.Thr263Ser | missense_variant | 7/22 | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000217 AC: 33AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251400Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135858
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727230
GnomAD4 genome ? AF: 0.000217 AC: 33AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74486
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 04, 2015 | - - |
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 263 of the VCL protein (p.Thr263Ser). This variant is present in population databases (rs142233726, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 468824). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 12, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 468824; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at