NM_012463.4:c.1590C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012463.4(ATP6V0A2):c.1590C>T(p.Pro530Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,614,242 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00096 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 9 hom. )

Consequence

ATP6V0A2
NM_012463.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.13

Publications

3 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=-0.67).

BP6

Variant 12-123744957-C-T is Benign according to our data. Variant chr12-123744957-C-T is described in ClinVar as Benign. ClinVar VariationId is 307588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000965 (147/152366) while in subpopulation EAS AF = 0.0224 (116/5190). AF 95% confidence interval is 0.019. There are 3 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.1590C>T	p.Pro530Pro	synonymous_variant	Exon 13 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.1590C>T	p.Pro530Pro	synonymous_variant	Exon 13 of 19		XP_024304678.1
ATP6V0A2	XM_024448911.2 link	c.1077C>T	p.Pro359Pro	synonymous_variant	Exon 9 of 16		XP_024304679.1
ATP6V0A2	XM_024448912.2 link	c.768C>T	p.Pro256Pro	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.1590C>T	p.Pro530Pro	synonymous_variant	Exon 13 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00177

AC:

445

AN:

251454

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0212

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000755

AC:

1103

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

567

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26136

East Asian (EAS)

AF:

0.0202

AC:

801

AN:

39700

South Asian (SAS)

AF:

0.000962

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000989

AC:

110

AN:

1111996

Other (OTH)

AF:

0.00103

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000965

AC:

147

AN:

152366

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.0224

AC:

116

AN:

5190

South Asian (SAS)

AF:

0.00124

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000416

Hom.:

Bravo

AF:

0.00120

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 24, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATP6V0A2-related disorder

Benign:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Jun 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG9 congenital disorder of glycosylation

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

-0.67

CADD

Benign

1.7

(source)

DANN

Benign

0.88

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(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