rs748404277
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017890.5(VPS13B):βc.6370_6371delβ(p.Met2124ValfsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000034 ( 0 hom. )
Consequence
VPS13B
NM_017890.5 frameshift
NM_017890.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.49
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
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 8-99699772-CAT-C is Pathogenic according to our data. Variant chr8-99699772-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242548.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.6370_6371del | p.Met2124ValfsTer44 | frameshift_variant | 36/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.6295_6296del | p.Met2099ValfsTer44 | frameshift_variant | 36/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.6295_6296del | p.Met2099ValfsTer44 | frameshift_variant | 36/62 | 1 | NM_152564.5 | P1 | |
VPS13B | ENST00000358544.7 | c.6370_6371del | p.Met2124ValfsTer44 | frameshift_variant | 36/62 | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251212Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135770
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461820Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727192
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74304
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Met2124Valfs*44) 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 (rs748404277, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with VPS13B-related conditions (PMID: 26395554, 29149870). This variant is also known as c.6295_6296delAT. ClinVar contains an entry for this variant (Variation ID: 242548). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2020 | Observed with another VPS13B variant on the opposite allele (in trans) in a patient with microcephaly and malformation of cortical development in published literature (Zillhardt et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29149870, 26395554) - |
Abnormality of the eye Uncertain:1
Uncertain significance, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
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