16-2519689-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The ENST00000330398.9(ATP6V0C):​c.412G>C​(p.Ala138Pro) 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 (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ATP6V0C
ENST00000330398.9 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.66
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity VATL_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000330398.9
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP6V0CNM_001694.4 linkuse as main transcriptc.412G>C p.Ala138Pro missense_variant 3/3 ENST00000330398.9 NP_001685.1
ATP6V0CNM_001198569.2 linkuse as main transcriptc.412G>C p.Ala138Pro missense_variant 4/4 NP_001185498.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP6V0CENST00000330398.9 linkuse as main transcriptc.412G>C p.Ala138Pro missense_variant 3/31 NM_001694.4 ENSP00000329757 P1
ATP6V0CENST00000564973.1 linkuse as main transcriptc.283G>C p.Ala95Pro missense_variant 2/22 ENSP00000454868
ATP6V0CENST00000565223.1 linkuse as main transcriptc.283G>C p.Ala95Pro missense_variant 3/33 ENSP00000457782
ATP6V0CENST00000568562.1 linkuse as main transcript downstream_gene_variant 3 ENSP00000454597

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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1004311). This variant has not been reported in the literature in individuals affected with ATP6V0C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 138 of the ATP6V0C protein (p.Ala138Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;T;T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D;.;D
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Benign
-0.55
T
MutationAssessor
Uncertain
2.1
M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.7
D;D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.025
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.90
MutPred
0.69
Gain of relative solvent accessibility (P = 0.09);.;.;
MVP
0.52
MPC
3.4
ClinPred
0.99
D
GERP RS
3.3
Varity_R
0.96
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2065898758; hg19: chr16-2569690; API