rs367543007

Positions:

• chr12-123754416-TCA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_012463.4(ATP6V0A2):​c.2176-3_2176-2delCA variant causes a splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V0A2 NM_012463.4 splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.31

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]

ENSG00000280300 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• PP5: Variant 12-123754416-TCA-T is Pathogenic according to our data. Variant chr12-123754416-TCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 21496.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.2176-3_2176-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.2056-3_2056-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant			XP_024304678.1
ATP6V0A2	XM_024448911.2	c.1663-3_1663-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant			XP_024304679.1
ATP6V0A2	XM_024448912.2	c.1354-3_1354-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant			XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.2176-3_2176-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_012463.4	ENSP00000332247.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cutis laxa with osteodystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Sep 23, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 17
DS_AL_spliceai		0.94		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs367543007; hg19: chr12-124238963;