Genetic Variant ATP12A:p.His2Asn (chr13-24680747-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001676.7(ATP12A):c.4C>A(p.His2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,348,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. H2Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

ATP12A
NM_001676.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.42

Publications

0 publications found

Variant links:

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]

ATP12A links:

ENSG00000303666 (HGNC:):

ENSG00000303666 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12189072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP12A	NM_001676.7 link	c.4C>A	p.His2Asn	missense_variant	Exon 1 of 23	ENST00000381946.5	NP_001667.4	P54707-1B4E0R9
ATP12A	NM_001185085.2 link	c.4C>A	p.His2Asn	missense_variant	Exon 1 of 23		NP_001172014.1	P54707-2B4E0R9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP12A	ENST00000381946.5 link	c.4C>A	p.His2Asn	missense_variant	Exon 1 of 23	1	NM_001676.7	ENSP00000371372.3	P54707-1
ATP12A	ENST00000218548.10 link	c.4C>A	p.His2Asn	missense_variant	Exon 1 of 23	1		ENSP00000218548.6	P54707-2
ENSG00000303666	ENST00000796402.1 link	n.72+3753G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.41e-7

AC:

AN:

1348728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665004

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27430

American (AMR)

AF:

0.00

AC:

AN:

31972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23872

East Asian (EAS)

AF:

0.00

AC:

AN:

31034

South Asian (SAS)

AF:

0.00

AC:

AN:

75840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4418

European-Non Finnish (NFE)

AF:

9.39e-7

AC:

AN:

1064422

Other (OTH)

AF:

0.00

AC:

AN:

56298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.5

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.21

T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.0

N;N

PhyloP100

-1.4

PrimateAI

Benign

0.35

PROVEAN

Benign

0.33

N;N

REVEL

Benign

0.22

Sift

Benign

0.32

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;B

Vest4

0.11

MutPred

0.19

Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);

MVP

0.81

MPC

0.24

ClinPred

0.30

GERP RS

0.30

PromoterAI

0.16

Neutral

(source)

Varity_R

0.047

gMVP

0.18

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over