rs386834113
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.8515C>T(p.Arg2839Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,784 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.8515C>T | p.Arg2839Ter | stop_gained | 46/62 | ENST00000358544.7 | NP_060360.3 | |
VPS13B | NM_152564.5 | c.8440C>T | p.Arg2814Ter | stop_gained | 46/62 | ENST00000357162.7 | NP_689777.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.8515C>T | p.Arg2839Ter | stop_gained | 46/62 | 1 | NM_017890.5 | ENSP00000351346 | ||
VPS13B | ENST00000357162.7 | c.8440C>T | p.Arg2814Ter | stop_gained | 46/62 | 1 | NM_152564.5 | ENSP00000349685 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250996Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135612
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461678Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727136
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74286
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:5
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 09, 2018 | Variant summary: VPS13B c.8515C>T (p.Arg2839X) 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 (e.g., p.Trp3649X and p.Pro3969fsX41). The variant allele was found at a frequency of 2e-05 in 245746 control chromosomes. c.8515C>T has been reported as a homozygous allele in the literature in individuals affected with Cohen Syndrome, indicating the variant is likely to be associated with disease. At least one publication reports experimental evidence showing a reduction of COH1 mRNA expression (10%-<30% of normal expression) and fragmented Golgi structures in patient cells (Seifert_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 17, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 16, 2023 | This sequence change creates a premature translational stop signal (p.Arg2839*) 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 (rs386834113, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 19006247). ClinVar contains an entry for this variant (Variation ID: 56694). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19006247, 23188044, 24334764, 30843084, 25525159, 31589614, 21865173) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at