rs80356751

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_012463.4(ATP6V0A2):c.294+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATP6V0A2
NM_012463.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 9.02

Publications

1 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:

ENSG00000286092 (HGNC:):

ENSG00000286092 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-123722449-G-A is Pathogenic according to our data. Variant chr12-123722449-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 21499.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.294+1G>A	splice_donor_variant, intron_variant	Intron 3 of 19	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.294+1G>A	splice_donor_variant, intron_variant	Intron 3 of 18		XP_024304678.1
LOC105370042	XR_945477.4 link	n.81+561C>T	intron_variant	Intron 1 of 2
LOC105370042	XR_945478.4 link	n.81+561C>T	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.294+1G>A		splice_donor_variant, intron_variant	Intron 3 of 19	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719458

African (AFR)

AF:

0.00

AC:

AN:

33118

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00

AC:

AN:

85918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095684

Other (OTH)

AF:

0.00

AC:

AN:

59772

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Cutis laxa with osteodystrophy

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Wrinkly skin syndrome

Pathogenic:1

Jan 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

Splicevardb

3.0

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over