chr12-123724668-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_012463.4(ATP6V0A2):c.309G>T(p.Lys103Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K103K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.211

Publications

7 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32015878).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000469 (685/1461642) while in subpopulation NFE AF = 0.000576 (640/1111852). AF 95% confidence interval is 0.000539. There are 0 homozygotes in GnomAdExome4. There are 323 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.309G>T	p.Lys103Asn	missense_variant	Exon 4 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.309G>T	p.Lys103Asn	missense_variant	Exon 4 of 19		XP_024304678.1
ATP6V0A2	XM_024448911.2 link	c.-116G>T		upstream_gene_variant			XP_024304679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.309G>T	p.Lys103Asn	missense_variant	Exon 4 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000135

AC:

AN:

251458

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000469

AC:

685

AN:

1461642

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

323

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000576

AC:

640

AN:

1111852

Other (OTH)

AF:

0.000729

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000256

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000312

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Uncertain:1

Apr 28, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.309G>T (p.K103N) alteration is located in exon 4 (coding exon 4) of the ATP6V0A2 gene. This alteration results from a G to T substitution at nucleotide position 309, causing the lysine (K) at amino acid position 103 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ALG9 congenital disorder of glycosylation

Uncertain:1

Aug 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 103 of the ATP6V0A2 protein (p.Lys103Asn). This variant is present in population databases (rs144499089, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ATP6V0A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 307578). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cutis laxa with osteodystrophy;C0406587:Wrinkly skin syndrome

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa with osteodystrophy

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

0.21

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.030

D;D

Polyphen

0.92

P;D

Vest4

0.46

MutPred

0.60

Loss of ubiquitination at K103 (P = 0.0059);Loss of ubiquitination at K103 (P = 0.0059);

MVP

0.69

MPC

0.74

ClinPred

0.50

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.43

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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