rs367543007

chr12-123754416-TCA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP3_Moderate PP5

The NM_012463.4(ATP6V0A2):c.2176-3_2176-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change involving the alteration of a conserved nucleotide. 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_polypyrimidine_tract, 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
ATP6V0A2	NM_012463.4	c.2176-3_2176-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.2056-3_2056-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant
ATP6V0A2	XM_024448911.2	c.1663-3_1663-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant
ATP6V0A2	XM_024448912.2	c.1354-3_1354-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.2176-3_2176-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012463.4	P1
	ENST00000623681.1	n.377_378del		non_coding_transcript_exon_variant	1/1

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;