13-24690412-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001676.7(ATP12A):c.621G>C(p.Glu207Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATP12A
NM_001676.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

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:

ENSG00000285806 (HGNC:):

ENSG00000285806 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27050588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP12A	NM_001676.7 link	c.621G>C	p.Glu207Asp	missense_variant	Exon 6 of 23	ENST00000381946.5	NP_001667.4	P54707-1B4E0R9
ATP12A	NM_001185085.2 link	c.621G>C	p.Glu207Asp	missense_variant	Exon 6 of 23		NP_001172014.1	P54707-2B4E0R9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP12A	ENST00000381946.5 link	c.621G>C	p.Glu207Asp	missense_variant	Exon 6 of 23	1	NM_001676.7	ENSP00000371372.3	P54707-1
ATP12A	ENST00000218548.10 link	c.621G>C	p.Glu207Asp	missense_variant	Exon 6 of 23	1		ENSP00000218548.6	P54707-2
ENSG00000285806	ENST00000782956.1 link	n.281-1324C>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251480

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41210

American (AMR)

AF:

0.00

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.621G>C (p.E207D) alteration is located in exon 6 (coding exon 6) of the ATP12A gene. This alteration results from a G to C substitution at nucleotide position 621, causing the glutamic acid (E) at amino acid position 207 to be replaced by an aspartic acid (D). 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

0.23

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

.;D

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.8

L;L

PhyloP100

1.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.065

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.032

B;B

Vest4

0.55

MutPred

0.48

Gain of catalytic residue at K209 (P = 0.0016);Gain of catalytic residue at K209 (P = 0.0016);

MVP

0.90

MPC

0.20

ClinPred

0.096

GERP RS

2.1

Varity_R

0.18

gMVP

0.59

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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13-24690412-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over