Genetic Variant VPS13C:p.Thr3716Ile (chr15-61854884-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1

The NM_020821.3(VPS13C):c.11147C>T(p.Thr3716Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,840 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: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

VPS13C
NM_020821.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00800

Variant links:

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]

VPS13C links:

ENSG00000259564 (HGNC:):

ENSG00000259564 links:

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ACMG classification

Classification made for transcript

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 (MetaRNN=0.025862306).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000263 (4/152148) while in subpopulation SAS AF= 0.000828 (4/4832). AF 95% confidence interval is 0.000282. There are 0 homozygotes in gnomad4. There are 1 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 link	c.11147C>T	p.Thr3716Ile	missense_variant	Exon 84 of 85	ENST00000644861.2	NP_065872.1	Q709C8-1
VPS13C	NM_017684.5 link	c.11018C>T	p.Thr3673Ile	missense_variant	Exon 82 of 83		NP_060154.3	Q709C8-3
LOC124903501	XR_007064668.1 link	n.159+5412G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13C	ENST00000644861.2 link	c.11147C>T	p.Thr3716Ile	missense_variant	Exon 84 of 85		NM_020821.3	ENSP00000493560.2		Q709C8-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250132

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000296

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460692

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.95

DANN

Benign

0.91

DEOGEN2

Benign

0.011

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.53

.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.48

.;N;N

REVEL

Benign

0.036

Sift

Benign

0.081

.;T;T

Polyphen

0.023

B;B;B

Vest4

0.15, 0.17

MutPred

0.26

Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);

MVP

0.37

MPC

0.025

ClinPred

0.015

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over