rs369100678
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_020821.3(VPS13C):āc.4165G>Cā(p.Gly1389Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,390,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_020821.3 missense, splice_region
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 |
---|---|---|---|---|---|---|---|
VPS13C | NM_020821.3 | c.4165G>C | p.Gly1389Arg | missense_variant, splice_region_variant | 37/85 | ENST00000644861.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13C | ENST00000644861.2 | c.4165G>C | p.Gly1389Arg | missense_variant, splice_region_variant | 37/85 | NM_020821.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.0000244 AC: 34AN: 1390618Hom.: 0 Cov.: 25 AF XY: 0.0000260 AC XY: 18AN XY: 693424
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive early-onset Parkinson disease 23 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 20, 2019 | - - |
Parkinson disease Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Brain and Spine Institute, INSERM | Nov 16, 2015 | - - |
Young-onset Parkinson disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 11, 2020 | The p.Gly1389Arg variant in VPS13C has been reported in 1 compound heterozygous individual with Parkinson disease (Lesage 2016 PMID: 26942284) and was absent from large population studies. It has also been reported in ClinVar (Variation ID 222070). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located in the first base of the exon, which is part of the 5ā splice region. Computational tools do not predict a splicing impact; however, RNA studies using patient's lymphocytes suggest a splicing impact (Lesage 2016 PMID: 26942284). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive parkinsonism. ACMG/AMP Criteria applied: PM2, PM3, PP3, PS3_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at