15-61958608-C-T

Variant names:

• chr15-61958608-C-T
• NM_020821.3:c.4165G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_020821.3(VPS13C):​c.4165G>A​(p.Gly1389Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,390,618 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 Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: VPS13C NM_020821.3 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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 Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius 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	c.4165G>A	p.Gly1389Ser	missense_variant, splice_region_variant	Exon 37 of 85	ENST00000644861.2	NP_065872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13C	ENST00000644861.2	c.4165G>A	p.Gly1389Ser	missense_variant, splice_region_variant	Exon 37 of 85		NM_020821.3	ENSP00000493560.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1390618 Hom.: 0 Cov.: 25 AF XY: 0.00000144 AC XY: 1 AN XY: 693424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T;.;T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	.;T;T;.;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L;L;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	.;N;N;.;N;N
REVEL	Benign	0.052
Sift	Benign	0.12	.;T;T;.;D;D
Polyphen		0.38	B;B;B;B;B;B
Vest4		0.21, 0.19, 0.24, 0.28
MutPred		0.22		Gain of phosphorylation at G1389 (P = 0.0336);.;Gain of phosphorylation at G1389 (P = 0.0336);Gain of phosphorylation at G1389 (P = 0.0336);Gain of phosphorylation at G1389 (P = 0.0336);.;
MVP		0.24
MPC		0.024
ClinPred		0.53	D
GERP RS		4.5
Varity_R		0.079
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: -14
DS_DL_spliceai		0.61		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-62250807;