rs180177354
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.1504C>T(p.Arg502Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,194 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017890.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.1504C>T | p.Arg502Ter | stop_gained | 11/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.1504C>T | p.Arg502Ter | stop_gained | 11/62 | ENST00000357162.7 | |
VPS13B | NM_015243.3 | c.1504C>T | p.Arg502Ter | stop_gained | 11/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.1504C>T | p.Arg502Ter | stop_gained | 11/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.1504C>T | p.Arg502Ter | stop_gained | 11/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151968Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251170Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135748
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461226Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726922
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 151968Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74220
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2022 | Variant summary: VPS13B c.1504C>T (p.Arg502X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.4411C>T (p.Arg1471X), c.7603C>T (p.Arg2535X), c.8515C>T (p.Arg2839X)). The variant allele was found at a frequency of 1.2e-05 in 251320 control chromosomes (gnomAD and Hennies_2004) and has been reported in the literature in individuals affected with Cohen Syndrome (example Hennies_2004, Seifert_2006, Tsangaris_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has a submitted clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Arg502*) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs180177354, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15154116, 16648375). ClinVar contains an entry for this variant (Variation ID: 68083). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at