rs559590419
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_017890.5(VPS13B):c.4186C>T(p.Gln1396Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,866 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1396Q) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.4186C>T | p.Gln1396Ter | stop_gained | 28/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.4224+595C>T | intron_variant | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.4186C>T | p.Gln1396Ter | stop_gained | 28/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.4224+595C>T | intron_variant | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151998Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251330Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135830
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727182
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change creates a premature translational stop signal (p.Gln1396*) 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 (rs559590419, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 553132). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 28, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.Q1396* in VPS13B (NM_017890.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Q1396* variant is observed in 2/30,612 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported previously to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at