12-123712593-A-C

Variant names:

• chr12-123712593-A-C
• rs758214692
• NM_012463.4:c.28A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012463.4(ATP6V0A2):​c.28A>C​(p.Met10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M10V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• 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

LOC105370042 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33243614).

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.28A>C	p.Met10Leu	missense	Exon 1 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.28A>C	p.Met10Leu	missense	Exon 1 of 20	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000613625.5	TSL:1	c.28A>C	p.Met10Leu	missense	Exon 1 of 9	ENSP00000482236.1	Q8TBM3
	ATP6V0A2	ENST00000540368.6	TSL:1	n.59A>C		non_coding_transcript_exon	Exon 1 of 18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449386 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720204

African (AFR) AF: 0.00 AC: 0 AN: 33212

American (AMR) AF: 0.00 AC: 0 AN: 43544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39176

South Asian (SAS) AF: 0.00 AC: 0 AN: 84552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107650

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		1.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.69	P
Vest4		0.47
MutPred		0.64		Gain of catalytic residue at L12 (P = 0.0032)
MVP		0.43
MPC		0.15
ClinPred		0.97	D
GERP RS		-0.0099
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.32
gMVP		0.73
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs758214692; hg19: chr12-124197140;