Genetic Variant ATP12A:p.Asn144Lys (chr13-24688522-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.432C>A(p.Asn144Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N144N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ATP12A
NM_001676.7 missense, splice_region

Scores

Splicing: ADA: 0.00008052

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.52

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:

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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=0.23908198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP12A	NM_001676.7 link	c.432C>A	p.Asn144Lys	missense_variant, splice_region_variant	Exon 4 of 23	ENST00000381946.5	NP_001667.4	P54707-1B4E0R9
ATP12A	NM_001185085.2 link	c.432C>A	p.Asn144Lys	missense_variant, splice_region_variant	Exon 4 of 23		NP_001172014.1	P54707-2B4E0R9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP12A	ENST00000381946.5 link	c.432C>A	p.Asn144Lys	missense_variant, splice_region_variant	Exon 4 of 23	1	NM_001676.7	ENSP00000371372.3		P54707-1
ATP12A	ENST00000218548.10 link	c.432C>A	p.Asn144Lys	missense_variant, splice_region_variant	Exon 4 of 23	1		ENSP00000218548.6		P54707-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1424726

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703836

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:

32614

American (AMR)

AF:

0.00

AC:

AN:

41998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24100

East Asian (EAS)

AF:

0.00

AC:

AN:

39012

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090582

Other (OTH)

AF:

0.00

AC:

AN:

58696

⚠️ 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

Pathogenic

0.72

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.29

CADD

Benign

1.0

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.75

.;D

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.52

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.5

H;H

PhyloP100

-1.5

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.045

B;P

Vest4

0.37

MutPred

0.53

Gain of catalytic residue at C149 (P = 0.0213);Gain of catalytic residue at C149 (P = 0.0213);

MVP

0.73

MPC

0.53

ClinPred

0.57

GERP RS

-10

Varity_R

0.23

gMVP

0.80

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000081

dbscSNV1_RF

Benign

0.040

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