rs139665824

chr15-62028419-G-Achr15-62028419-G-Cchr15-62028419-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6 BP7 BS1

The NM_020821.3(VPS13C):c.387C>T(p.Gly129=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,612,688 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: VPS13C NM_020821.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002027
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.612

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-62028419-G-A is Benign according to our data. Variant chr15-62028419-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547944.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.612 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000559 (85/152024) while in subpopulation AMR AF= 0.000918 (14/15246). AF 95% confidence interval is 0.000554. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13C	NM_020821.3	c.387C>T	p.Gly129=	splice_region_variant, synonymous_variant	6/85	ENST00000644861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13C	ENST00000644861.2	c.387C>T	p.Gly129=	splice_region_variant, synonymous_variant	6/85		NM_020821.3	P3
VPS13C	ENST00000249837.7	c.386-4899C>T		intron_variant		1
VPS13C	ENST00000395898.3	c.386-4899C>T		intron_variant		1
VPS13C	ENST00000645819.1	c.387C>T	p.Gly129=	splice_region_variant, synonymous_variant	6/82			A2

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000598 AC: 150 AN: 250890 Hom.: 0 AF XY: 0.000693 AC XY: 94 AN XY: 135608

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000618

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000470 AC: 686 AN: 1460664 Hom.: 1 Cov.: 30 AF XY: 0.000501 AC XY: 364 AN XY: 726672

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00456

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74246

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000744 Hom.: 1

Bravo AF: 0.000718

EpiCase AF: 0.000820

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	VPS13C: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 27, 2023	- -

Autosomal recessive early-onset Parkinson disease 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	9.4
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139665824; hg19: chr15-62320618;