12-123712584-A-G

Variant names:

• chr12-123712584-A-G
• NM_012463.4:c.19A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012463.4(ATP6V0A2):​c.19A>G​(p.Ser7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.891

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]

LOC105370042 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32602978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.19A>G	p.Ser7Gly	missense_variant	Exon 1 of 20	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.19A>G	p.Ser7Gly	missense_variant	Exon 1 of 19		XP_024304678.1
LOC105370042	XR_945477.4	n.*182T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.19A>G	p.Ser7Gly	missense_variant	Exon 1 of 20	1	NM_012463.4	ENSP00000332247.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jul 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

ALG9 congenital disorder of glycosylation Uncertain:1

Jun 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ATP6V0A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 7 of the ATP6V0A2 protein (p.Ser7Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	0.0045
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.48
Sift	Benign	0.032	D;.
Sift4G	Uncertain	0.031	D;T
Polyphen		0.55	P;B
Vest4		0.18
MutPred		0.58		Gain of catalytic residue at L12 (P = 3e-04);Gain of catalytic residue at L12 (P = 3e-04);
MVP		0.64
MPC		0.15
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.27
gMVP		0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-124197131;