rs79134187

Positions:

• chr12-123743867-A-G

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.1121A>G​(p.Lys374Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,614,174 control chromosomes in the GnomAD database, including 238 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. K374E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (134 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.18

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=0.010434598).
• BP6: Variant 12-123743867-A-G is Benign according to our data. Variant chr12-123743867-A-G is described in ClinVar as [Benign]. Clinvar id is 95517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123743867-A-G is described in Lovd as [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.1121A>G	p.Lys374Arg	missense_variant	10/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.1121A>G	p.Lys374Arg	missense_variant	10/19
ATP6V0A2	XM_024448911.2	c.608A>G	p.Lys203Arg	missense_variant	6/16
ATP6V0A2	XM_024448912.2	c.299A>G	p.Lys100Arg	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.1121A>G	p.Lys374Arg	missense_variant	10/20	1	NM_012463.4	P1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3377 AN: 152166 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0113 AC: 2846 AN: 251486 Hom.: 75 AF XY: 0.00926 AC XY: 1258 AN XY: 135914

Gnomad AFR exome AF: 0.0593

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00718

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00425 AC: 6212 AN: 1461890 Hom.: 134 Cov.: 32 AF XY: 0.00404 AC XY: 2941 AN XY: 727246

Gnomad4 AFR exome AF: 0.0569

Gnomad4 AMR exome AF: 0.0422

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00443

Gnomad4 SAS exome AF: 0.00481

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00609

GnomAD4 genome AF: 0.0222 AC: 3380 AN: 152284 Hom.: 104 Cov.: 32 AF XY: 0.0232 AC XY: 1730 AN XY: 74460

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.0551

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00597

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0104 Hom.: 22

Bravo AF: 0.0267

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0583 AC: 257

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0101 AC: 1232

Asia WGS AF: 0.0110 AC: 37 AN: 3478

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

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

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	0.070
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.11	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.099	B;.
Vest4		0.37
MPC		0.14
ClinPred		0.031	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs79134187; hg19: chr12-124228414;