chr15-61854543-T-C

Position:

• chr15-61854543-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020821.3(VPS13C):​c.11176A>G​(p.Ile3726Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,614,094 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (32 hom.)
• Consequence: VPS13C NM_020821.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.28

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004065752).
• BP6: Variant 15-61854543-T-C is Benign according to our data. Variant chr15-61854543-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 791595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-61854543-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00337 (514/152314) while in subpopulation NFE AF= 0.00544 (370/68026). AF 95% confidence interval is 0.00498. There are 3 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13C	NM_020821.3	c.11176A>G	p.Ile3726Val	missense_variant	85/85	ENST00000644861.2
LOC124903501	XR_007064668.1	n.159+5071T>C		intron_variant, non_coding_transcript_variant
VPS13C	NM_017684.5	c.11047A>G	p.Ile3683Val	missense_variant	83/83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13C	ENST00000644861.2	c.11176A>G	p.Ile3726Val	missense_variant	85/85		NM_020821.3	P3
	ENST00000642740.1	n.172+5071T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00397 AC: 997 AN: 251144 Hom.: 5 AF XY: 0.00400 AC XY: 543 AN XY: 135722

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00487 AC: 7116 AN: 1461780 Hom.: 32 Cov.: 30 AF XY: 0.00486 AC XY: 3534 AN XY: 727204

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00662

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00558

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.00337 AC: 514 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00350 AC XY: 261 AN XY: 74490

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00544

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00457 Hom.: 2

Bravo AF: 0.00339

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00403 AC: 489

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.00545

EpiControl AF: 0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	VPS13C: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.8	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.46	.;N;N
REVEL	Benign	0.20
Sift	Benign	0.17	.;T;T
Polyphen		0.99	D;D;D
Vest4		0.17, 0.18
MVP		0.60
MPC		0.023
ClinPred		0.026	T
GERP RS		5.4
Varity_R		0.055
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs115819951; hg19: chr15-62146742;