rs386834095
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_017890.5(VPS13B):c.5615dup(p.Ser1873GlufsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000124 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. DK1871D?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
VPS13B
NM_017890.5 frameshift
NM_017890.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.66
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 12 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 8-99642128-C-CA is Pathogenic according to our data. Variant chr8-99642128-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 848471.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.5615dup | p.Ser1873GlufsTer9 | frameshift_variant | 34/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.5540dup | p.Ser1848GlufsTer9 | frameshift_variant | 34/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.5540dup | p.Ser1848GlufsTer9 | frameshift_variant | 34/62 | 1 | NM_152564.5 | P1 | |
VPS13B | ENST00000358544.7 | c.5615dup | p.Ser1873GlufsTer9 | frameshift_variant | 34/62 | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461818Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727202
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 05, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 848471). This variant is also known as 5613_5614insT. This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15141358). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1873Glufs*9) 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). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at