12-123744882-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012463.4(ATP6V0A2):c.1515T>C(p.Asn505Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,613,844 control chromosomes in the GnomAD database, including 347,608 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 39330 hom., cov: 32)

Exomes 𝑓: 0.65 ( 308278 hom. )

Consequence

ATP6V0A2
NM_012463.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00005240

Clinical Significance

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

Conservation

PhyloP100: -1.06

Publications

28 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 12-123744882-T-C is Benign according to our data. Variant chr12-123744882-T-C is described in ClinVar as Benign. ClinVar VariationId is 95520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.1515T>C	p.Asn505Asn	splice_region_variant, synonymous_variant	Exon 13 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.1515T>C	p.Asn505Asn	splice_region_variant, synonymous_variant	Exon 13 of 19		XP_024304678.1
ATP6V0A2	XM_024448911.2 link	c.1002T>C	p.Asn334Asn	splice_region_variant, synonymous_variant	Exon 9 of 16		XP_024304679.1
ATP6V0A2	XM_024448912.2 link	c.693T>C	p.Asn231Asn	splice_region_variant, synonymous_variant	Exon 6 of 13		XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.1515T>C	p.Asn505Asn	splice_region_variant, synonymous_variant	Exon 13 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.712

AC:

108223

AN:

152036

Hom.:

39267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.830

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.663

Gnomad EAS

AF:

0.950

Gnomad SAS

AF:

0.681

Gnomad FIN

AF:

0.681

Gnomad MID

AF:

0.621

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.700

GnomAD2 exomes

AF:

0.698

AC:

175478

AN:

251466

AF XY:

0.686

show subpopulations

Gnomad AFR exome

AF:

0.836

Gnomad AMR exome

AF:

0.808

Gnomad ASJ exome

AF:

0.662

Gnomad EAS exome

AF:

0.949

Gnomad FIN exome

AF:

0.674

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.667

GnomAD4 exome

AF:

0.645

AC:

942865

AN:

1461688

Hom.:

308278

Cov.:

AF XY:

0.645

AC XY:

468668

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.828

AC:

27706

AN:

33474

American (AMR)

AF:

0.804

AC:

35960

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.663

AC:

17337

AN:

26134

East Asian (EAS)

AF:

0.957

AC:

37991

AN:

39696

South Asian (SAS)

AF:

0.660

AC:

56933

AN:

86256

European-Finnish (FIN)

AF:

0.677

AC:

36182

AN:

53418

Middle Eastern (MID)

AF:

0.643

AC:

3711

AN:

5768

European-Non Finnish (NFE)

AF:

0.617

AC:

686549

AN:

1111826

Other (OTH)

AF:

0.671

AC:

40496

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

20978

41957

62935

83914

104892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18616

37232

55848

74464

93080

<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:

0.712

AC:

108349

AN:

152156

Hom.:

39330

Cov.:

AF XY:

0.714

AC XY:

53130

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.830

AC:

34451

AN:

41506

American (AMR)

AF:

0.759

AC:

11609

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.663

AC:

2299

AN:

3470

East Asian (EAS)

AF:

0.950

AC:

4923

AN:

5184

South Asian (SAS)

AF:

0.682

AC:

3290

AN:

4824

European-Finnish (FIN)

AF:

0.681

AC:

7207

AN:

10586

Middle Eastern (MID)

AF:

0.623

AC:

182

AN:

292

European-Non Finnish (NFE)

AF:

0.624

AC:

42432

AN:

67978

Other (OTH)

AF:

0.704

AC:

1483

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1578

3156

4734

6312

7890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.655

Hom.:

130258

Bravo

AF:

0.726

Asia WGS

AF:

0.831

AC:

2889

AN:

3478

EpiCase

AF:

0.622

EpiControl

AF:

0.623

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jul 25, 2012

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

- -

Cutis laxa with osteodystrophy

Benign:2

Jan 12, 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

-0.82

CADD

Benign

0.20

(source)

DANN

Benign

0.44

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=74/26

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000052

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 6

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