rs144539572
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.436C>T(p.Arg146Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,609,236 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R146R) has been classified as Likely benign. 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.436C>T | p.Arg146Ter | stop_gained | 5/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.436C>T | p.Arg146Ter | stop_gained | 5/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.436C>T | p.Arg146Ter | stop_gained | 5/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.436C>T | p.Arg146Ter | stop_gained | 5/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251172Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135772
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1457192Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11AN XY: 725270
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74268
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change creates a premature translational stop signal (p.Arg146*) 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 (rs144539572, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 20656880, 23188044). ClinVar contains an entry for this variant (Variation ID: 370440). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 09, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2021 | Variant summary: VPS13B c.436C>T (p.Arg146X) 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. At-least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251172 control chromosomes. c.436C>T has been reported in the literature in at-least two individuals affected with Cohen Syndrome, one of whom as a critically ill infant, underwent extensive clinical and diagnostic workup by whole genome sequencing (example, El Chehadeh_2010, Duplomb_2019, Wang_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2022 | 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: 25525159, 23188044, 20656880, 30843084, 32005694) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at