Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS1

The NM_020821.3(VPS13C):c.387C>T(p.Gly129Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,612,688 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 1 hom. )

Consequence

VPS13C
NM_020821.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0002027

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.612

Publications

3 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 15-62028419-G-A is Benign according to our data. Variant chr15-62028419-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547944.

BP7

Synonymous conserved (PhyloP=0.612 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000559 (85/152024) while in subpopulation AMR AF = 0.000918 (14/15246). AF 95% confidence interval is 0.000554. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS13C	NM_020821.3	MANE Select	c.387C>T	p.Gly129Gly	splice_region synonymous	Exon 6 of 85	NP_065872.1
VPS13C	NM_001018088.3		c.387C>T	p.Gly129Gly	splice_region synonymous	Exon 6 of 82	NP_001018098.1
VPS13C	NM_017684.5		c.386-4899C>T		intron	N/A	NP_060154.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS13C	ENST00000644861.2	MANE Select	c.387C>T	p.Gly129Gly	splice_region synonymous	Exon 6 of 85	ENSP00000493560.2
VPS13C	ENST00000249837.7	TSL:1	c.386-4899C>T		intron	N/A	ENSP00000249837.3
VPS13C	ENST00000395898.3	TSL:1	c.386-4899C>T		intron	N/A	ENSP00000379235.3

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.000918

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000598

AC:

150

AN:

250890

AF XY:

0.000693

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000618

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.000470

AC:

686

AN:

1460664

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

364

AN XY:

726672

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33392

American (AMR)

AF:

0.000470

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00456

AC:

119

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.000302

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000380

AC:

422

AN:

1111170

Other (OTH)

AF:

0.00116

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.000559

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41398

American (AMR)

AF:

0.000918

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

67980

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000724

Hom.:

Bravo

AF:

0.000718

EpiCase

AF:

0.000820

EpiControl

AF:

0.000889

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal recessive early-onset Parkinson disease 23 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.4

(source)

DANN

Benign

0.81

PhyloP100

0.61

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.038

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

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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over