rs869320761

Positions:

• chr15-62013058-C-CTCTG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020821.3(VPS13C):​c.805_806insCAGA​(p.Arg269ThrfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13C NM_020821.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.52

Genes affected

VPS13C (HGNC:23594): (vacuolar protein sorting 13 homolog C) Involved in mitochondrion organization and negative regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization. Located in cytosol and mitochondrial outer membrane. Implicated in Parkinson's disease 23. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 15-62013058-C-CTCTG is Pathogenic according to our data. Variant chr15-62013058-C-CTCTG is described in ClinVar as [Pathogenic]. Clinvar id is 224604.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13C	NM_020821.3	c.805_806insCAGA	p.Arg269ThrfsTer14	frameshift_variant	11/85	ENST00000644861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13C	ENST00000644861.2	c.805_806insCAGA	p.Arg269ThrfsTer14	frameshift_variant	11/85		NM_020821.3	P3
VPS13C	ENST00000249837.7	c.676_677insCAGA	p.Arg226ThrfsTer14	frameshift_variant	9/83	1
VPS13C	ENST00000395898.3	c.676_677insCAGA	p.Arg226ThrfsTer14	frameshift_variant	9/80	1
VPS13C	ENST00000645819.1	c.805_806insCAGA	p.Arg269ThrfsTer14	frameshift_variant	11/82			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320761; hg19: chr15-62305257;