rs774276857

Positions:

• chr12-123756860-G-A

Variant summary

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

The NM_012463.4(ATP6V0A2):​c.2339G>A​(p.Arg780His) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.01

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]

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=0.38682148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.2339G>A	p.Arg780His	missense_variant	19/20	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.2219G>A	p.Arg740His	missense_variant	18/19		XP_024304678.1
ATP6V0A2	XM_024448911.2	c.1826G>A	p.Arg609His	missense_variant	15/16		XP_024304679.1
ATP6V0A2	XM_024448912.2	c.1517G>A	p.Arg506His	missense_variant	12/13		XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.2339G>A	p.Arg780His	missense_variant	19/20	1	NM_012463.4	ENSP00000332247	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251476 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALG9 congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP6V0A2 protein function. ClinVar contains an entry for this variant (Variation ID: 533136). This variant has not been reported in the literature in individuals affected with ATP6V0A2-related conditions. This variant is present in population databases (rs774276857, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 780 of the ATP6V0A2 protein (p.Arg780His). -

Cutis laxa with osteodystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.014	B;.;.
Vest4		0.77
MutPred		0.55		Gain of catalytic residue at D782 (P = 2e-04);.;.;
MVP		0.72
MPC		0.25
ClinPred		0.40	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.060
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs774276857; hg19: chr12-124241407; COSMIC: COSV57750177; COSMIC: COSV57750177;