dbSNP rs369100678: VPS13C:p.Gly1389Cys (chr15-61958608-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_020821.3(VPS13C):c.4165G>T(p.Gly1389Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1389R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

VPS13C
NM_020821.3 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive early-onset Parkinson disease 23
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
young-onset Parkinson disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

VPS13C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-61958608-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 222070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13C	NM_020821.3 link	c.4165G>T	p.Gly1389Cys	missense_variant, splice_region_variant	Exon 37 of 85	ENST00000644861.2	NP_065872.1	Q709C8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13C	ENST00000644861.2 link	c.4165G>T	p.Gly1389Cys	missense_variant, splice_region_variant	Exon 37 of 85		NM_020821.3	ENSP00000493560.2		Q709C8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1390616

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693422

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29822

American (AMR)

AF:

0.00

AC:

AN:

35482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24988

East Asian (EAS)

AF:

0.00

AC:

AN:

37494

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068944

Other (OTH)

AF:

0.00

AC:

AN:

57768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

T;.;T;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

.;D;D;.;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.35

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.;M;M;M;.

PhyloP100

3.4

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

.;N;N;.;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.017

.;D;D;.;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.46, 0.48, 0.49, 0.52

MutPred

0.34

Loss of disorder (P = 0.0741);.;Loss of disorder (P = 0.0741);Loss of disorder (P = 0.0741);Loss of disorder (P = 0.0741);.;

MVP

0.50

MPC

0.13

ClinPred

0.94

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.22

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.50

Position offset: -14

DS_DL_spliceai

0.73

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over