chr12-123712654-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012463.4(ATP6V0A2):​c.89G>A​(p.Gly30Asp) 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 (★). Synonymous variant affecting the same amino acid position (i.e. G30G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35
Variant links:
Genes affected
ATP6V0A2 (HGNC:18481): (ATPase H+ transporting V0 subunit a2) The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP6V0A2NM_012463.4 linkuse as main transcriptc.89G>A p.Gly30Asp missense_variant 1/20 ENST00000330342.8
ATP6V0A2XM_024448910.2 linkuse as main transcriptc.89G>A p.Gly30Asp missense_variant 1/19

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP6V0A2ENST00000330342.8 linkuse as main transcriptc.89G>A p.Gly30Asp missense_variant 1/201 NM_012463.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cutis laxa with osteodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Benign
0.74
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Pathogenic
4.5
H;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.1
D;.
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.73
MutPred
0.78
Gain of catalytic residue at L26 (P = 0.0076);Gain of catalytic residue at L26 (P = 0.0076);
MVP
0.72
MPC
0.76
ClinPred
1.0
D
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.87
gMVP
0.91

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

LitVar

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

Other links and lift over

dbSNP: rs1956303931; hg19: chr12-124197201; API