NM_012463.4:c.426T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_012463.4(ATP6V0A2):c.426T>C(p.Asn142Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,609,970 control chromosomes in the GnomAD database, including 337,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34045 hom., cov: 31)

Exomes 𝑓: 0.64 ( 303029 hom. )

Consequence

ATP6V0A2
NM_012463.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.07

Publications

22 publications found

Variant links:

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]

ATP6V0A2 Gene-Disease associations (from GenCC):

wrinkly skin syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
autosomal recessive cutis laxa type 2, classic type
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet
autosomal recessive cutis laxa type 2A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ATP6V0A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 12-123724785-T-C is Benign according to our data. Variant chr12-123724785-T-C is described in ClinVar as Benign. ClinVar VariationId is 95523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.426T>C	p.Asn142Asn	synonymous_variant	Exon 4 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448911.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16		XP_024304679.1
ATP6V0A2	XM_024448910.2 link	c.426T>C	p.Asn142Asn	synonymous_variant	Exon 4 of 19		XP_024304678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.426T>C	p.Asn142Asn	synonymous_variant	Exon 4 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101003

AN:

151328

Hom.:

34002

Cov.:

show subpopulations

Gnomad AFR

AF:

0.679

Gnomad AMI

AF:

0.518

Gnomad AMR

AF:

0.743

Gnomad ASJ

AF:

0.652

Gnomad EAS

AF:

0.947

Gnomad SAS

AF:

0.680

Gnomad FIN

AF:

0.678

Gnomad MID

AF:

0.621

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.672

GnomAD2 exomes

AF:

0.686

AC:

172482

AN:

251346

AF XY:

0.677

show subpopulations

Gnomad AFR exome

AF:

0.689

Gnomad AMR exome

AF:

0.801

Gnomad ASJ exome

AF:

0.655

Gnomad EAS exome

AF:

0.947

Gnomad FIN exome

AF:

0.673

Gnomad NFE exome

AF:

0.621

Gnomad OTH exome

AF:

0.661

GnomAD4 exome

AF:

0.641

AC:

934233

AN:

1458526

Hom.:

303029

Cov.:

AF XY:

0.641

AC XY:

464933

AN XY:

725758

show subpopulations

African (AFR)

AF:

0.677

AC:

22610

AN:

33418

American (AMR)

AF:

0.796

AC:

35611

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

17085

AN:

26092

East Asian (EAS)

AF:

0.955

AC:

37868

AN:

39660

South Asian (SAS)

AF:

0.659

AC:

56816

AN:

86196

European-Finnish (FIN)

AF:

0.677

AC:

36114

AN:

53312

Middle Eastern (MID)

AF:

0.634

AC:

3655

AN:

5762

European-Non Finnish (NFE)

AF:

0.617

AC:

684677

AN:

1109090

Other (OTH)

AF:

0.660

AC:

39797

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

16695

33390

50084

66779

83474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18518

37036

55554

74072

92590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.668

AC:

101103

AN:

151444

Hom.:

34045

Cov.:

AF XY:

0.671

AC XY:

49648

AN XY:

73940

show subpopulations

African (AFR)

AF:

0.679

AC:

28027

AN:

41290

American (AMR)

AF:

0.743

AC:

11308

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.652

AC:

2262

AN:

3468

East Asian (EAS)

AF:

0.948

AC:

4878

AN:

5148

South Asian (SAS)

AF:

0.681

AC:

3274

AN:

4808

European-Finnish (FIN)

AF:

0.678

AC:

7073

AN:

10426

Middle Eastern (MID)

AF:

0.627

AC:

183

AN:

292

European-Non Finnish (NFE)

AF:

0.623

AC:

42208

AN:

67784

Other (OTH)

AF:

0.677

AC:

1421

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1655

3310

4964

6619

8274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.647

Hom.:

19820

Bravo

AF:

0.677

Asia WGS

AF:

0.818

AC:

2840

AN:

3478

EpiCase

AF:

0.621

EpiControl

AF:

0.621

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 11, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cutis laxa with osteodystrophy

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Wrinkly skin syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ALG9 congenital disorder of glycosylation

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.033

(source)

DANN

Benign

0.59

PhyloP100

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over