rs9920256

Variant names:

• chr15-61907381-T-A
• rs9920256
• NM_020821.3:c.8988A>T

Your query was ambiguous. Multiple possible variants found:

• chr15-61907381-T-A
• chr15-61907381-T-C

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.8988A>T​(p.Pro2996Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,613,738 control chromosomes in the GnomAD database, including 1,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2996P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.052 (359 hom., cov: 32)
  • Exomes 𝑓: 0.029 (900 hom.)
• Consequence: VPS13C NM_020821.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.339
• Publications: 7 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: 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)

ENSG00000259564 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-61907381-T-A is Benign according to our data. Variant chr15-61907381-T-A is described in ClinVar as Benign. ClinVar VariationId is 1288720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13C	NM_020821.3	MANE Select	c.8988A>T	p.Pro2996Pro	synonymous	Exon 66 of 85	NP_065872.1	Q709C8-1
	VPS13C	NM_017684.5		c.8859A>T	p.Pro2953Pro	synonymous	Exon 64 of 83	NP_060154.3
	VPS13C	NM_001018088.3		c.8988A>T	p.Pro2996Pro	synonymous	Exon 66 of 82	NP_001018098.1	Q709C8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13C	ENST00000644861.2	MANE Select	c.8988A>T	p.Pro2996Pro	synonymous	Exon 66 of 85	ENSP00000493560.2	Q709C8-1
	VPS13C	ENST00000249837.7	TSL:1	c.8859A>T	p.Pro2953Pro	synonymous	Exon 64 of 83	ENSP00000249837.3	Q709C8-3
	VPS13C	ENST00000395898.3	TSL:1	c.8859A>T	p.Pro2953Pro	synonymous	Exon 64 of 80	ENSP00000379235.3	Q709C8-4

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7934 AN: 152196 Hom.: 359 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0347 AC: 8711 AN: 250960 AF XY: 0.0319

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0967

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0276

GnomAD4 exome AF: 0.0285 AC: 41664 AN: 1461424 Hom.: 900 Cov.: 31 AF XY: 0.0279 AC XY: 20284 AN XY: 726992

African (AFR) AF: 0.122 AC: 4086 AN: 33462

American (AMR) AF: 0.0326 AC: 1458 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 494 AN: 26116

East Asian (EAS) AF: 0.0995 AC: 3950 AN: 39688

South Asian (SAS) AF: 0.0157 AC: 1357 AN: 86218

European-Finnish (FIN) AF: 0.0145 AC: 775 AN: 53384

Middle Eastern (MID) AF: 0.0349 AC: 201 AN: 5764

European-Non Finnish (NFE) AF: 0.0247 AC: 27430 AN: 1111728

Other (OTH) AF: 0.0317 AC: 1913 AN: 60372

GnomAD4 genome AF: 0.0521 AC: 7939 AN: 152314 Hom.: 359 Cov.: 32 AF XY: 0.0510 AC XY: 3800 AN XY: 74492

African (AFR) AF: 0.117 AC: 4857 AN: 41556

American (AMR) AF: 0.0339 AC: 519 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.0866 AC: 449 AN: 5186

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4834

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0245 AC: 1666 AN: 68022

Other (OTH) AF: 0.0435 AC: 92 AN: 2116

Alfa AF: 0.0185 Hom.: 21

Bravo AF: 0.0576

Asia WGS AF: 0.0680 AC: 238 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	VPS13C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.7
DANN	Benign	0.39
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs9920256; hg19: chr15-62199580; COSMIC: COSV51155237;