chr8-99156693-C-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.2158C>T(p.Gln720*) 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 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
Publications
- Cohen syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.2158C>T | p.Gln720* | stop_gained | Exon 15 of 62 | ENST00000358544.7 | NP_060360.3 | |
VPS13B | NM_152564.5 | c.2158C>T | p.Gln720* | stop_gained | Exon 15 of 62 | ENST00000357162.7 | NP_689777.3 | |
VPS13B | NM_015243.3 | c.2158C>T | p.Gln720* | stop_gained | Exon 15 of 18 | NP_056058.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.2158C>T | p.Gln720* | stop_gained | Exon 15 of 62 | 1 | NM_017890.5 | ENSP00000351346.2 | ||
VPS13B | ENST00000357162.7 | c.2158C>T | p.Gln720* | stop_gained | Exon 15 of 62 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251332 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461720Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727162 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:5
PVS1, PM2, PM3 -
- -
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*). -
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. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at