rs139665824

Variant names:

• chr15-62028419-G-A
• rs139665824
• NM_020821.3:c.387C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-62028419-G-A
• chr15-62028419-G-C
• chr15-62028419-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.Gly129Gly) 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. 3/3 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. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13C	NM_020821.3	c.387C>T	p.Gly129Gly	splice_region_variant, synonymous_variant	Exon 6 of 85	ENST00000644861.2	NP_065872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13C	ENST00000644861.2	c.387C>T	p.Gly129Gly	splice_region_variant, synonymous_variant	Exon 6 of 85		NM_020821.3	ENSP00000493560.2
VPS13C	ENST00000249837.7	c.386-4899C>T		intron_variant	Intron 5 of 82	1		ENSP00000249837.3
VPS13C	ENST00000395898.3	c.386-4899C>T		intron_variant	Intron 5 of 79	1		ENSP00000379235.3
VPS13C	ENST00000645819.1	c.387C>T	p.Gly129Gly	splice_region_variant, synonymous_variant	Exon 6 of 82			ENSP00000496179.1

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

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VPS13C: BP4, BP7 -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive early-onset Parkinson disease 23 Uncertain:1

Apr 12, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;