NM_020821.3:c.625-103T>G

Variant names:

• chr15-62020641-A-C
• rs4143844
• NM_020821.3:c.625-103T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020821.3(VPS13C):​c.625-103T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,083,474 control chromosomes in the GnomAD database, including 3,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (355 hom., cov: 32)
  • Exomes 𝑓: 0.079 (3127 hom.)
• Consequence: VPS13C NM_020821.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06
• Publications: 12 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-62020641-A-C is Benign according to our data. Variant chr15-62020641-A-C is described in ClinVar as Benign. ClinVar VariationId is 1234177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13C	NM_020821.3	MANE Select	c.625-103T>G		intron	N/A	NP_065872.1
	VPS13C	NM_017684.5		c.496-103T>G		intron	N/A	NP_060154.3
	VPS13C	NM_001018088.3		c.625-103T>G		intron	N/A	NP_001018098.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13C	ENST00000644861.2	MANE Select	c.625-103T>G		intron	N/A	ENSP00000493560.2
	VPS13C	ENST00000249837.7	TSL:1	c.496-103T>G		intron	N/A	ENSP00000249837.3
	VPS13C	ENST00000395898.3	TSL:1	c.496-103T>G		intron	N/A	ENSP00000379235.3

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9055 AN: 151942 Hom.: 355 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0645

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.0361

Gnomad SAS AF: 0.0669

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0862

Gnomad OTH AF: 0.0705

GnomAD4 exome AF: 0.0791 AC: 73712 AN: 931414 Hom.: 3127 AF XY: 0.0790 AC XY: 37373 AN XY: 473294

African (AFR) AF: 0.0236 AC: 497 AN: 21046

American (AMR) AF: 0.0488 AC: 1154 AN: 23656

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 915 AN: 18300

East Asian (EAS) AF: 0.0340 AC: 1122 AN: 33008

South Asian (SAS) AF: 0.0664 AC: 3669 AN: 55244

European-Finnish (FIN) AF: 0.0432 AC: 1910 AN: 44182

Middle Eastern (MID) AF: 0.0822 AC: 366 AN: 4452

European-Non Finnish (NFE) AF: 0.0884 AC: 61044 AN: 690642

Other (OTH) AF: 0.0742 AC: 3035 AN: 40884

GnomAD4 genome AF: 0.0595 AC: 9050 AN: 152060 Hom.: 355 Cov.: 32 AF XY: 0.0571 AC XY: 4246 AN XY: 74360

African (AFR) AF: 0.0225 AC: 935 AN: 41532

American (AMR) AF: 0.0644 AC: 981 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3466

East Asian (EAS) AF: 0.0356 AC: 184 AN: 5166

South Asian (SAS) AF: 0.0669 AC: 323 AN: 4826

European-Finnish (FIN) AF: 0.0377 AC: 401 AN: 10626

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0862 AC: 5856 AN: 67896

Other (OTH) AF: 0.0697 AC: 147 AN: 2108

Alfa AF: 0.0753 Hom.: 793

Bravo AF: 0.0601

Asia WGS AF: 0.0470 AC: 162 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.9
DANN	Benign	0.55
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4143844; hg19: chr15-62312840;