Genetic Variant NM_020821.3:c.11056G>C (chr15-61856306-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020821.3(VPS13C):c.11056G>C(p.Val3686Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. V3686M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VPS13C
NM_020821.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.748

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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:

ENSG00000259564 (HGNC:):

ENSG00000259564 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036155343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020821.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13C	NM_020821.3	MANE Select	c.11056G>C	p.Val3686Leu	missense	Exon 83 of 85	NP_065872.1	Q709C8-1
	VPS13C	NM_017684.5		c.10927G>C	p.Val3643Leu	missense	Exon 81 of 83	NP_060154.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS13C	ENST00000644861.2	MANE Select	c.11056G>C	p.Val3686Leu	missense	Exon 83 of 85	ENSP00000493560.2	Q709C8-1
VPS13C	ENST00000249837.7	TSL:1	c.10927G>C	p.Val3643Leu	missense	Exon 81 of 83	ENSP00000249837.3	Q709C8-3
VPS13C	ENST00000560637.5	TSL:1	n.1425G>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111468

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.37

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.015

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.65

M_CAP

Benign

0.0049

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

-0.75

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.32

REVEL

Benign

0.025

Sift

Benign

0.38

Polyphen

0.0

Vest4

0.099

MutPred

0.36

Loss of sheet (P = 0.1398)

MVP

0.067

MPC

0.023

ClinPred

0.017

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over