12-123727875-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_012463.4(ATP6V0A2):c.614C>T(p.Ala205Val) variant causes a missense change. The variant allele was found at a frequency of 0.000383 in 1,614,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 5.90

Publications

6 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):

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

ATP6V0A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030753493).

BP6

Variant 12-123727875-C-T is Benign according to our data. Variant chr12-123727875-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 307580.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000388 (59/152206) while in subpopulation AMR AF = 0.00105 (16/15282). AF 95% confidence interval is 0.000656. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012463.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	NM_012463.4	MANE Select	c.614C>T	p.Ala205Val	missense	Exon 6 of 20	NP_036595.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.614C>T	p.Ala205Val	missense	Exon 6 of 20	ENSP00000332247.2
ATP6V0A2	ENST00000613625.5	TSL:1	c.614C>T	p.Ala205Val	missense	Exon 6 of 9	ENSP00000482236.1
ATP6V0A2	ENST00000540368.6	TSL:1	n.645C>T		non_coding_transcript_exon	Exon 6 of 18

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000469

AC:

118

AN:

251474

AF XY:

0.000508

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000382

AC:

559

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000406

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00919

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000259

AC:

288

AN:

1112000

Other (OTH)

AF:

0.000729

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

132

165

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:

0.000388

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41450

American (AMR)

AF:

0.00105

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68042

Other (OTH)

AF:

0.00143

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.000597

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG9 congenital disorder of glycosylation (1)

Cutis laxa with osteodystrophy (1)

Cutis laxa with osteodystrophy;C0406587:Wrinkly skin syndrome (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Benign

0.096

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.038

MetaRNN

Benign

0.031

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.0

PhyloP100

5.9

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.47

Sift

Benign

0.15

Sift4G

Benign

0.33

Polyphen

0.0080

Vest4

0.70

MVP

0.68

MPC

0.61

ClinPred

0.045

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.65

Mutation Taster

=70/30

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over