rs139509075

chr12-123756905-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_012463.4(ATP6V0A2):c.2384C>T(p.Ala795Val) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A795T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.15

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024079114).
• BP6: Variant 12-123756905-C-T is Benign according to our data. Variant chr12-123756905-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446885.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00042 (64/152314) while in subpopulation AFR AF= 0.00144 (60/41566). AF 95% confidence interval is 0.00115. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A2	NM_012463.4	c.2384C>T	p.Ala795Val	missense_variant	19/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.2264C>T	p.Ala755Val	missense_variant	18/19
ATP6V0A2	XM_024448911.2	c.1871C>T	p.Ala624Val	missense_variant	15/16
ATP6V0A2	XM_024448912.2	c.1562C>T	p.Ala521Val	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.2384C>T	p.Ala795Val	missense_variant	19/20	1	NM_012463.4	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251490 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135916

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000784 AC XY: 57 AN XY: 727240

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 24 AN XY: 74486

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000540

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 16, 2017

- -

ALG9 congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.0088
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.024	D;T;T
Sift4G	Benign	0.076	T;T;T
Polyphen		0.13	B;.;.
Vest4		0.49
MVP		0.71
MPC		0.38
ClinPred		0.036	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs139509075; hg19: chr12-124241452;