rs138886791

chr12-123754482-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_012463.4(ATP6V0A2):c.2238C>T(p.Cys746=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,160 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: ATP6V0A2 NM_012463.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.19

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-123754482-C-T is Benign according to our data. Variant chr12-123754482-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210384.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr12-123754482-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00149 (227/152314) while in subpopulation NFE AF= 0.00259 (176/68018). AF 95% confidence interval is 0.00227. There are 0 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A2	NM_012463.4	c.2238C>T	p.Cys746=	synonymous_variant	18/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.2118C>T	p.Cys706=	synonymous_variant	17/19
ATP6V0A2	XM_024448911.2	c.1725C>T	p.Cys575=	synonymous_variant	14/16
ATP6V0A2	XM_024448912.2	c.1416C>T	p.Cys472=	synonymous_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.2238C>T	p.Cys746=	synonymous_variant	18/20	1	NM_012463.4	P1
	ENST00000623681.1	n.313G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00157 AC: 396 AN: 251480 Hom.: 2 AF XY: 0.00170 AC XY: 231 AN XY: 135916

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00171 AC: 2502 AN: 1461846 Hom.: 5 Cov.: 30 AF XY: 0.00174 AC XY: 1267 AN XY: 727230

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74482

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATP6V0A2: BP4, BS2 -

Cutis laxa with osteodystrophy Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

ATP6V0A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

ALG9 congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Benign	0.68

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: rs138886791; hg19: chr12-124239029;