15-61854884-G-C

Variant names:

• chr15-61854884-G-C
• rs374500259
• NM_020821.3:c.11147C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020821.3(VPS13C):​c.11147C>G​(p.Thr3716Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS13C NM_020821.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800

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]

ENSG00000259564 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03424588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13C	NM_020821.3	c.11147C>G	p.Thr3716Ser	missense_variant	Exon 84 of 85	ENST00000644861.2	NP_065872.1
VPS13C	NM_017684.5	c.11018C>G	p.Thr3673Ser	missense_variant	Exon 82 of 83		NP_060154.3
LOC124903501	XR_007064668.1	n.159+5412G>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13C	ENST00000644861.2	c.11147C>G	p.Thr3716Ser	missense_variant	Exon 84 of 85		NM_020821.3	ENSP00000493560.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250132 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460692 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.16
DANN	Benign	0.33
DEOGEN2	Benign	0.0085	T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.38	.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N;.;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.12	.;N;N
REVEL	Benign	0.024
Sift	Benign	0.72	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.086
MutPred		0.28		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);
MVP		0.34
MPC		0.022
ClinPred		0.029	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs374500259; hg19: chr15-62147083;