rs17883456

chr12-123756959-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_012463.4(ATP6V0A2):c.2438C>T(p.Ala813Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,614,172 control chromosomes in the GnomAD database, including 968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A813A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (79 hom., cov: 31)
  • Exomes 𝑓: 0.032 (889 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.91

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0110394955).
• BP6: Variant 12-123756959-C-T is Benign according to our data. Variant chr12-123756959-C-T is described in ClinVar as [Benign]. Clinvar id is 95521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123756959-C-T is described in Lovd as [Benign]. Variant chr12-123756959-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A2	NM_012463.4	c.2438C>T	p.Ala813Val	missense_variant	19/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.2318C>T	p.Ala773Val	missense_variant	18/19
ATP6V0A2	XM_024448911.2	c.1925C>T	p.Ala642Val	missense_variant	15/16
ATP6V0A2	XM_024448912.2	c.1616C>T	p.Ala539Val	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.2438C>T	p.Ala813Val	missense_variant	19/20	1	NM_012463.4	P1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3819 AN: 152182 Hom.: 79 Cov.: 31

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0282 AC: 7088 AN: 251488 Hom.: 156 AF XY: 0.0289 AC XY: 3930 AN XY: 135920

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0414

Gnomad NFE exome AF: 0.0366

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0324 AC: 47368 AN: 1461872 Hom.: 889 Cov.: 31 AF XY: 0.0322 AC XY: 23386 AN XY: 727246

Gnomad4 AFR exome AF: 0.00705

Gnomad4 AMR exome AF: 0.0174

Gnomad4 ASJ exome AF: 0.0574

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0411

Gnomad4 NFE exome AF: 0.0349

Gnomad4 OTH exome AF: 0.0320

GnomAD4 genome AF: 0.0250 AC: 3814 AN: 152300 Hom.: 79 Cov.: 31 AF XY: 0.0248 AC XY: 1850 AN XY: 74468

Gnomad4 AFR AF: 0.00700

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0499

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0407

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0337 Hom.: 172

Bravo AF: 0.0227

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0335 AC: 129

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.0352 AC: 303

ExAC AF: 0.0284 AC: 3442

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0356

EpiControl AF: 0.0355

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in gnomAD (Ashkenazi Jewish population) and about 3% in other populations in Exome Aggregation Consortium. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

ALG9 congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cutis laxa with osteodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.9	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.93
MPC		0.68
ClinPred		0.071	T
GERP RS		5.7
Varity_R		0.53
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17883456; hg19: chr12-124241506; COSMIC: COSV57748957; COSMIC: COSV57748957;