Genetic Variant ATP12A:c.9+1G>C (chr13-24680753-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_001676.7(ATP12A):c.9+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATP12A
NM_001676.7 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.39

Publications

1 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: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11057692 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP12A	NM_001676.7 link	c.9+1G>C		splice_donor_variant, intron_variant	Intron 1 of 22	ENST00000381946.5	NP_001667.4	P54707-1B4E0R9
ATP12A	NM_001185085.2 link	c.9+1G>C		splice_donor_variant, intron_variant	Intron 1 of 22		NP_001172014.1	P54707-2B4E0R9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP12A	ENST00000381946.5 link	c.9+1G>C	splice_donor_variant, intron_variant	Intron 1 of 22	1	NM_001676.7	ENSP00000371372.3	P54707-1
ATP12A	ENST00000218548.10 link	c.9+1G>C	splice_donor_variant, intron_variant	Intron 1 of 22	1		ENSP00000218548.6	P54707-2
ENSG00000303666	ENST00000796402.1 link	n.72+3747C>G	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

94542

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1347446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

664316

African (AFR)

AF:

0.00

AC:

AN:

27386

American (AMR)

AF:

0.00

AC:

AN:

31658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23822

East Asian (EAS)

AF:

0.00

AC:

AN:

30924

South Asian (SAS)

AF:

0.00

AC:

AN:

75624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4524

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1063864

Other (OTH)

AF:

0.00

AC:

AN:

56208

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.77

PhyloP100

2.4

GERP RS

3.1

PromoterAI

-0.29

Neutral

(source)

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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