NM_012463.4:c.294+393T>G

Variant names:

• chr12-123722841-T-G
• rs10734905
• NM_012463.4:c.294+393T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012463.4(ATP6V0A2):​c.294+393T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 151,538 control chromosomes in the GnomAD database, including 33,779 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (33779 hom., cov: 28)
• Consequence: ATP6V0A2 NM_012463.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 4 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):

• 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)

ENSG00000286092 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	NM_012463.4	MANE Select	c.294+393T>G		intron	N/A	NP_036595.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.294+393T>G		intron	N/A	ENSP00000332247.2
	ATP6V0A2	ENST00000613625.5	TSL:1	c.294+393T>G		intron	N/A	ENSP00000482236.1
	ATP6V0A2	ENST00000540368.6	TSL:1	n.325+393T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100566 AN: 151420 Hom.: 33735 Cov.: 28

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.670

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

GnomAD4 genome AF: 0.664 AC: 100668 AN: 151538 Hom.: 33779 Cov.: 28 AF XY: 0.669 AC XY: 49533 AN XY: 74038

African (AFR) AF: 0.678 AC: 28007 AN: 41284

American (AMR) AF: 0.742 AC: 11295 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2264 AN: 3470

East Asian (EAS) AF: 0.947 AC: 4849 AN: 5120

South Asian (SAS) AF: 0.680 AC: 3244 AN: 4770

European-Finnish (FIN) AF: 0.679 AC: 7135 AN: 10514

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.616 AC: 41801 AN: 67856

Other (OTH) AF: 0.674 AC: 1419 AN: 2104

Alfa AF: 0.657 Hom.: 5741

Bravo AF: 0.673

Asia WGS AF: 0.819 AC: 2845 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		-1.2
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10734905; hg19: chr12-124207388;