rs777593389
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.2158C>T(p.Gln720Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000103 in 1,461,720 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. Q720Q) 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.2158C>T | p.Gln720Ter | stop_gained | 15/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.2158C>T | p.Gln720Ter | stop_gained | 15/62 | ENST00000357162.7 | |
VPS13B | NM_015243.3 | c.2158C>T | p.Gln720Ter | stop_gained | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.2158C>T | p.Gln720Ter | stop_gained | 15/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.2158C>T | p.Gln720Ter | stop_gained | 15/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251332Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461720Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727162
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change creates a premature translational stop signal (p.Gln720*) 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 (rs777593389, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 26938784). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 369684). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 11, 2022 | PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 21, 2015 | This single nucleotide substitution results in a premature stop codon at position 720, NP_060360.3(VPS13B): p.(Gln720*). This is a novel variant not reported in disease or population databases. It was identified in trans with a second previously published pathogenic variant in this gene, p.(Trp963*). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at