rs367543008

Variant names:

• chr12-123756823-G-A
• rs367543008
• NM_012463.4:c.2302G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012463.4(ATP6V0A2):​c.2302G>A​(p.Asp768Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.14
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2302G>A	p.Asp768Asn	missense	Exon 19 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.2302G>A	p.Asp768Asn	missense	Exon 19 of 20	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000858646.1		c.2182G>A	p.Asp728Asn	missense	Exon 18 of 19	ENSP00000528705.1
	ATP6V0A2	ENST00000544833.1	TSL:2	c.148G>A	p.Asp50Asn	missense	Exon 2 of 3	ENSP00000441143.1	F5GX48

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.036
Eigen_PC	Benign	0.050
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.73	N
PhyloP100		8.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.043	B
Vest4		0.55
MutPred		0.60		Gain of catalytic residue at V769 (P = 6e-04)
MVP		0.64
MPC		0.24
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.22
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs367543008; hg19: chr12-124241370;