13-24688522-C-G

Variant names:

• chr13-24688522-C-G
• rs199568379
• NM_001676.7:c.432C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001676.7(ATP12A):​c.432C>G​(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 0.00000254 in 1,576,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP12A NM_001676.7 missense, splice_region
• Scores: Splicing: ADA: 0.0002148
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 2 publications found

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

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=0.26485497).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001676.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP12A	NM_001676.7	MANE Select	c.432C>G	p.Asn144Lys	missense splice_region	Exon 4 of 23	NP_001667.4
	ATP12A	NM_001185085.2		c.432C>G	p.Asn144Lys	missense splice_region	Exon 4 of 23	NP_001172014.1	P54707-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP12A	ENST00000381946.5	TSL:1 MANE Select	c.432C>G	p.Asn144Lys	missense splice_region	Exon 4 of 23	ENSP00000371372.3	P54707-1
	ATP12A	ENST00000218548.10	TSL:1	c.432C>G	p.Asn144Lys	missense splice_region	Exon 4 of 23	ENSP00000218548.6	P54707-2
	ATP12A	ENST00000911814.1		c.229-740C>G		intron	N/A	ENSP00000581873.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000444 AC: 1 AN: 225164 AF XY: 0.00000830

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: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424728 Hom.: 0 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 703838

African (AFR) AF: 0.00 AC: 0 AN: 32614

American (AMR) AF: 0.00 AC: 0 AN: 41998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39012

South Asian (SAS) AF: 0.00 AC: 0 AN: 79764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090582

Other (OTH) AF: 0.0000170 AC: 1 AN: 58696

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.92
DANN	Benign	0.94
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		-1.5
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.045	B
Vest4		0.37
MutPred		0.53		Gain of catalytic residue at C149 (P = 0.0213)
MVP		0.73
MPC		0.53
ClinPred		0.36	T
GERP RS		-10
Varity_R		0.23
gMVP		0.80
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.18
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

Other links and lift over

dbSNP: rs199568379; hg19: chr13-25262660;