rs80356756

Variant names:

• chr12-123748778-CA-C
• rs80356756
• NM_012463.4:c.1929delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_012463.4(ATP6V0A2):​c.1929delA​(p.Gln645ArgfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V0A2 NM_012463.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -1.76
• Publications: 1 publications found

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: G2P, Orphanet, Genomics England PanelApp
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-123748778-CA-C is Pathogenic according to our data. Variant chr12-123748778-CA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 21495.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1929delA	p.Gln645ArgfsTer39	frameshift	Exon 15 of 20	NP_036595.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.1929delA	p.Gln645ArgfsTer39	frameshift	Exon 15 of 20	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000540368.6	TSL:1	n.1960delA		non_coding_transcript_exon	Exon 15 of 18
	ATP6V0A2	ENST00000858646.1		c.1929delA	p.Gln645ArgfsTer7	frameshift	Exon 15 of 19	ENSP00000528705.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cutis laxa with osteodystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80356756; hg19: chr12-124233325;