16-2519325-G-A

Position:

• chr16-2519325-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The ENST00000330398.9(ATP6V0C):​c.187G>A​(p.Gly63Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G63A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP6V0C ENST00000330398.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.89

Genes affected

ATP6V0C (HGNC:855): (ATPase H+ transporting V0 subunit c) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. This gene encodes the V0 subunit c. Alternative splicing results in transcript variants. Pseudogenes have been identified on chromosomes 6 and 17. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain V-type proton ATPase 16 kDa proteolipid subunit c (size 154) in uniprot entity VATL_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000330398.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2519326-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2575304.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0C	NM_001694.4	c.187G>A	p.Gly63Ser	missense_variant	2/3	ENST00000330398.9	NP_001685.1
ATP6V0C	NM_001198569.2	c.187G>A	p.Gly63Ser	missense_variant	3/4		NP_001185498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0C	ENST00000330398.9	c.187G>A	p.Gly63Ser	missense_variant	2/3	1	NM_001694.4	ENSP00000329757	P1
ATP6V0C	ENST00000568562.1	c.134G>A	p.Trp45Ter	stop_gained	2/3	3		ENSP00000454597
ATP6V0C	ENST00000564973.1	c.58G>A	p.Gly20Ser	missense_variant	1/2	2		ENSP00000454868
ATP6V0C	ENST00000565223.1	c.58G>A	p.Gly20Ser	missense_variant	2/3	3		ENSP00000457782

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2024

The c.187G>A (p.G63S) alteration is located in exon 2 (coding exon 2) of the ATP6V0C gene. This alteration results from a G to A substitution at nucleotide position 187, causing the glycine (G) at amino acid position 63 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;.;D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	A;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.63		Gain of glycosylation at G63 (P = 0.1276);.;.;
MVP		0.50
MPC		2.9
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.98

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2569326;