rs1554560735
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.8117_8118del(p.Gly2706AlafsTer29) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
VPS13B
NM_017890.5 frameshift
NM_017890.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.55
Genes affected
VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-99809474-GGT-G is Pathogenic according to our data. Variant chr8-99809474-GGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.8117_8118del | p.Gly2706AlafsTer29 | frameshift_variant | 44/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.8042_8043del | p.Gly2681AlafsTer29 | frameshift_variant | 44/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.8042_8043del | p.Gly2681AlafsTer29 | frameshift_variant | 44/62 | 1 | NM_152564.5 | P1 | |
VPS13B | ENST00000358544.7 | c.8117_8118del | p.Gly2706AlafsTer29 | frameshift_variant | 44/62 | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461740Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727178
GnomAD4 exome
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727178
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 459250). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly2706Alafs*29) 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). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 08, 2015 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 16, 2020 | PVS1, PM2 - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at