12-123744756-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012463.4(ATP6V0A2):​c.1486G>C​(p.Ala496Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. A496T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.148
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13394922).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP6V0A2NM_012463.4 linkc.1486G>C p.Ala496Pro missense_variant Exon 12 of 20 ENST00000330342.8 NP_036595.2 Q9Y487
ATP6V0A2XM_024448910.2 linkc.1486G>C p.Ala496Pro missense_variant Exon 12 of 19 XP_024304678.1
ATP6V0A2XM_024448911.2 linkc.973G>C p.Ala325Pro missense_variant Exon 8 of 16 XP_024304679.1
ATP6V0A2XM_024448912.2 linkc.664G>C p.Ala222Pro missense_variant Exon 5 of 13 XP_024304680.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP6V0A2ENST00000330342.8 linkc.1486G>C p.Ala496Pro missense_variant Exon 12 of 20 1 NM_012463.4 ENSP00000332247.2 Q9Y487

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461892
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727248
show subpopulations
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:
0.00000180
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
0.087
BayesDel_addAF
Benign
-0.094
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
0.39
DANN
Benign
0.79
DEOGEN2
Benign
0.18
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.56
T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-0.52
N
REVEL
Benign
0.19
Sift
Benign
0.25
T
Sift4G
Benign
0.27
T
Polyphen
0.055
B
Vest4
0.23
MutPred
0.41
Gain of catalytic residue at P494 (P = 8e-04);
MVP
0.22
MPC
0.26
ClinPred
0.16
T
GERP RS
-4.2
Varity_R
0.050
gMVP
0.69

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: chr12-124229303; API