13-24691056-G-A

Position:

• chr13-24691056-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001676.7(ATP12A):​c.874G>A​(p.Val292Ile) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP12A NM_001676.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

Genes affected

ATP12A (HGNC:13816): (ATPase H+/K+ transporting non-gastric alpha2 subunit) The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This gene encodes a catalytic subunit of the ouabain-sensitive H+/K+ -ATPase that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for potassium absorption in various tissues. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25281334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP12A	NM_001676.7	c.874G>A	p.Val292Ile	missense_variant	8/23	ENST00000381946.5	NP_001667.4
ATP12A	NM_001185085.2	c.892G>A	p.Val298Ile	missense_variant	8/23		NP_001172014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP12A	ENST00000381946.5	c.874G>A	p.Val292Ile	missense_variant	8/23	1	NM_001676.7	ENSP00000371372	A1
ATP12A	ENST00000218548.10	c.892G>A	p.Val298Ile	missense_variant	8/23	1		ENSP00000218548	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.892G>A (p.V298I) alteration is located in exon 8 (coding exon 8) of the ATP12A gene. This alteration results from a G to A substitution at nucleotide position 892, causing the valine (V) at amino acid position 298 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.41	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.98	D;P
Vest4		0.086
MutPred		0.44		.;Gain of catalytic residue at S287 (P = 0);
MVP		0.74
MPC		0.20
ClinPred		0.76	D
GERP RS		5.0
Varity_R		0.32
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1220548988; hg19: chr13-25265194;