rs74922060

chr12-123737249-G-Achr12-123737249-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012463.4(ATP6V0A2):c.1016G>A(p.Arg339His) variant causes a missense change. The variant allele was found at a frequency of 0.00668 in 1,614,096 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R339C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (105 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (138 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.95

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037205517).
• BP6: Variant 12-123737249-G-A is Benign according to our data. Variant chr12-123737249-G-A is described in ClinVar as [Benign]. Clinvar id is 95516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123737249-G-A is described in Lovd as [Benign]. Variant chr12-123737249-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A2	NM_012463.4	c.1016G>A	p.Arg339His	missense_variant	9/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.1016G>A	p.Arg339His	missense_variant	9/19
ATP6V0A2	XM_024448911.2	c.503G>A	p.Arg168His	missense_variant	5/16
ATP6V0A2	XM_024448912.2	c.194G>A	p.Arg65His	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.1016G>A	p.Arg339His	missense_variant	9/20	1	NM_012463.4	P1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3420 AN: 152112 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0118 AC: 2959 AN: 251340 Hom.: 73 AF XY: 0.00978 AC XY: 1328 AN XY: 135854

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00723

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00503 AC: 7352 AN: 1461866 Hom.: 138 Cov.: 31 AF XY: 0.00479 AC XY: 3480 AN XY: 727236

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.0421

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00456

Gnomad4 SAS exome AF: 0.00485

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00649

GnomAD4 genome AF: 0.0225 AC: 3423 AN: 152230 Hom.: 105 Cov.: 32 AF XY: 0.0235 AC XY: 1748 AN XY: 74442

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.0544

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00651 Hom.: 11

Bravo AF: 0.0271

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.0572 AC: 252

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.0106 AC: 1288

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00302

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	GeneDx	Mar 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	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2012	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2015	- -

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	Benign	0.091
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;D
Eigen	Benign	0.16
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.032	D;.;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.72	P;D;.
Vest4		0.58
MPC		0.73
ClinPred		0.033	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.79

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

Other links and lift over

dbSNP: rs74922060; hg19: chr12-124221796; COSMIC: COSV57750265; COSMIC: COSV57750265;