rs180177374
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_017890.5(VPS13B):c.11907dup(p.Ser3970GlnfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A3968A) has been classified as Likely benign.
Frequency
Consequence
NM_017890.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.11907dup | p.Ser3970GlnfsTer22 | frameshift_variant | 62/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.11832dup | p.Ser3945GlnfsTer22 | frameshift_variant | 62/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.11832dup | p.Ser3945GlnfsTer22 | frameshift_variant | 62/62 | 1 | NM_152564.5 | P1 | |
VPS13B | ENST00000358544.7 | c.11907dup | p.Ser3970GlnfsTer22 | frameshift_variant | 62/62 | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251404Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135876
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74286
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2023 | ClinVar contains an entry for this variant (Variation ID: 56644). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Lys3991Leufs*23) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15141358, 16648375). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs749120462, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ser3970Glnfs*22) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the VPS13B protein. - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Jul 25, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2015 | The c.11907dupC pathogenic variant in the VPS13B gene has been reported previously in association with Cohen syndrome (Kolehmainen et al., 2004; Seifert et al., 2006). The c.11907dupC variant causes a frameshift starting with codon Serine 3970, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Ser3970GlnfsX22. This variant is predicted to cause loss of normal protein function through protein truncation. Furthermore, c.11907dupC was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.11907dupC as a pathogenic variant. - |
Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at