12-123712552-C-T

Variant names:

Variant summary

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

The ENST00000540368.6(ATP6V0A2):n.18C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,562,770 control chromosomes in the GnomAD database, including 111,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10274 hom., cov: 32)

Exomes 𝑓: 0.37 ( 101260 hom. )

Consequence

ATP6V0A2
ENST00000540368.6 non_coding_transcript_exon

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.43

Publications

13 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:

LOC105370042 (HGNC:):

LOC105370042 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=-0.48).

BP6

Variant 12-123712552-C-T is Benign according to our data. Variant chr12-123712552-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.-14C>T	5_prime_UTR_variant	Exon 1 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.-14C>T	5_prime_UTR_variant	Exon 1 of 19		XP_024304678.1
LOC105370042	XR_945477.4 link	n.*214G>A	downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.-14C>T		5_prime_UTR_variant	Exon 1 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.359

AC:

54506

AN:

151840

Hom.:

10267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.407

Gnomad AMI

AF:

0.513

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.0569

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.385

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.354

GnomAD2 exomes

AF:

0.322

AC:

54591

AN:

169792

AF XY:

0.330

show subpopulations

Gnomad AFR exome

AF:

0.439

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.0587

Gnomad FIN exome

AF:

0.310

Gnomad NFE exome

AF:

0.396

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.372

AC:

525012

AN:

1410818

Hom.:

101260

Cov.:

AF XY:

0.371

AC XY:

259445

AN XY:

699290

show subpopulations

African (AFR)

AF:

0.423

AC:

13482

AN:

31886

American (AMR)

AF:

0.210

AC:

8141

AN:

38848

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8137

AN:

25176

East Asian (EAS)

AF:

0.0468

AC:

1719

AN:

36702

South Asian (SAS)

AF:

0.337

AC:

27498

AN:

81662

European-Finnish (FIN)

AF:

0.304

AC:

12897

AN:

42396

Middle Eastern (MID)

AF:

0.372

AC:

1964

AN:

5280

European-Non Finnish (NFE)

AF:

0.395

AC:

430310

AN:

1090398

Other (OTH)

AF:

0.357

AC:

20864

AN:

58470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

17068

34136

51205

68273

85341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13330

26660

39990

53320

66650

<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:

0.359

AC:

54545

AN:

151952

Hom.:

10274

Cov.:

AF XY:

0.354

AC XY:

26279

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.407

AC:

16902

AN:

41484

American (AMR)

AF:

0.270

AC:

4123

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1135

AN:

3468

East Asian (EAS)

AF:

0.0569

AC:

293

AN:

5150

South Asian (SAS)

AF:

0.313

AC:

1511

AN:

4828

European-Finnish (FIN)

AF:

0.297

AC:

3133

AN:

10544

Middle Eastern (MID)

AF:

0.380

AC:

111

AN:

292

European-Non Finnish (NFE)

AF:

0.385

AC:

26132

AN:

67882

Other (OTH)

AF:

0.349

AC:

738

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1783

3565

5348

7130

8913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.364

Hom.:

1832

Bravo

AF:

0.358

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

Jan 08, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis Laxa, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Meckel-Gruber syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa with osteodystrophy

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.4

PromoterAI

-0.075

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

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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