rs786204456
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_152564.5(VPS13B):c.11831_11841delCCAGCTGTTCTinsG(p.Pro3944ArgfsTer41) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_152564.5 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.11906_11916delCCAGCTGTTCTinsG | p.Pro3969ArgfsTer41 | frameshift_variant, missense_variant | Exon 62 of 62 | ENST00000358544.7 | NP_060360.3 | |
VPS13B | NM_152564.5 | c.11831_11841delCCAGCTGTTCTinsG | p.Pro3944ArgfsTer41 | frameshift_variant, missense_variant | Exon 62 of 62 | ENST00000357162.7 | NP_689777.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.11906_11916delCCAGCTGTTCTinsG | p.Pro3969ArgfsTer41 | frameshift_variant, missense_variant | Exon 62 of 62 | 1 | NM_017890.5 | ENSP00000351346.2 | ||
VPS13B | ENST00000357162.7 | c.11831_11841delCCAGCTGTTCTinsG | p.Pro3944ArgfsTer41 | frameshift_variant, missense_variant | Exon 62 of 62 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:5
Variant summary: VPS13B c.11906_11916delinsG (p.Pro3969ArgfsX41) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.3e-06 in 318714 control chromosomes (gnomAD and Haque_2016). c.11906_11916delinsG has been reported in the literature in one individual who was undergoing whole gnomic sequencing (Reuter_2018). The report does not provide unequivocal conclusions about association of the variant with Cohen Syndrome. However, VPS13B c.11906_11915delCCAGCTGTTC, resulting in a similar mutant protein (p.Pro3969LeufsX41), has been reported in one patient with Cohen Syndrome (Kolehmainen_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical-significance assessments for this variant have been submitted to ClinVar after 2014. One classified the variant as pathogenic and the other as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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not provided Pathogenic:1
The c.11906_11916del11insG variant in the VPS13B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.11906_11916del11insG variant causes a frameshift starting with codon Proline 3969, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Pro3969ArgfsX41. This variant is predicted to cause loss of normal protein function through protein truncation. The c.11906_11916del11insG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.11906_11916del11insG as a likely pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at