rs1399961

Positions:

• chr12-123726235-T-A
• chr12-123726235-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012463.4(ATP6V0A2):​c.471T>A​(p.Ser157Arg) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S157S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.67

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044239968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.471T>A	p.Ser157Arg	missense_variant	5/20	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.471T>A	p.Ser157Arg	missense_variant	5/19		XP_024304678.1
ATP6V0A2	XM_024448911.2	c.8+1444T>A		intron_variant			XP_024304679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.471T>A	p.Ser157Arg	missense_variant	5/20	1	NM_012463.4	ENSP00000332247	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461260 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 726966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.010
DANN	Benign	0.82
DEOGEN2	Benign	0.18	T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.24	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.16	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.70	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.28	T;.;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.14
MutPred		0.47		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;
MVP		0.15
MPC		0.21
ClinPred		0.14	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.23

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: rs1399961; hg19: chr12-124210782;