chr1-160127692-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_000702.4(ATP1A2):c.889G>A(p.Ala297Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A297A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ATP1A2
NM_000702.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 9.97

Publications

7 publications found

Variant links:

Genes affected

ATP1A2 (HGNC:800): (ATPase Na+/K+ transporting subunit alpha 2) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]

ATP1A2 Gene-Disease associations (from GenCC):

hemiplegic migraine-developmental and epileptic encephalopathy spectrum
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
migraine, familial hemiplegic, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
alternating hemiplegia of childhood 1
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
developmental and epileptic encephalopathy 98
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
alternating hemiplegia of childhood
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial or sporadic hemiplegic migraine
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ATP1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000702.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ATP1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.7713 (above the threshold of 3.09). Trascript score misZ: 6.824 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 98, fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, migraine, familial hemiplegic, 2, alternating hemiplegia of childhood, alternating hemiplegia of childhood 1, familial or sporadic hemiplegic migraine, hemiplegic migraine-developmental and epileptic encephalopathy spectrum.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.817

PP5

Variant 1-160127692-G-A is Pathogenic according to our data. Variant chr1-160127692-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 430293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4 link	c.889G>A	p.Ala297Thr	missense_variant	Exon 8 of 23	ENST00000361216.8	NP_000693.1	P50993A0A0S2Z3W6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP1A2	ENST00000361216.8 link	c.889G>A	p.Ala297Thr	missense_variant	Exon 8 of 23	1	NM_000702.4	ENSP00000354490.3	P50993
ATP1A2	ENST00000392233.7 link	c.889G>A	p.Ala297Thr	missense_variant	Exon 8 of 23	5		ENSP00000376066.3	B1AKY9
ATP1A2	ENST00000447527.1 link	c.19G>A	p.Ala7Thr	missense_variant	Exon 1 of 16	2		ENSP00000411705.1	H0Y7C1
ATP1A2	ENST00000472488.5 link	n.992G>A		non_coding_transcript_exon_variant	Exon 8 of 20	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251442

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

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

African (AFR)

AF:

0.0000240

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy 98

Pathogenic:1

Apr 22, 2025

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been observed in individuals with ATP1A2-related conditions (PubMed: 31737037, 32345385, 33794876, 35231114). In at least two individuals, the variant has been observed to be de novo (PubMed: 33794876, 35231114). The REVEL score suggests that the variant may deleteriously affect the original protein function. -

not provided

Pathogenic:1

Jul 14, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Also reported in one individual with post-traumatic hemiplegic migraine and another individual with dystonia in the published literature (Cobb-Pitstick et al., 2020; Graziola et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33794876, 31737037, 32345385, 35231114) -

ATP1A2-related disorder

Pathogenic:1

Jun 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP1A2 c.889G>A variant is predicted to result in the amino acid substitution p.Ala297Thr. This variant was reported in an individual with dystonia (Table 1: Graziola et al 2019. PubMed ID: 31737037) and found in individuals with hemiplegia/alternating migraine of childhood (Cobb-Pitstick K et al 2020. PubMed ID: 32345385; reported as de novo in Huang D et al 2021. PubMed ID: 33794876; reported as de novo in Table S1: Duan J et al 2022. PubMed ID: 35231114). At PreventionGenetics, we have seen this variant occur de novo in an individual with hemiplegic events undergoing epilepsy testing (internal data). This variant is reported in a single individual of African descent (1/16,256 alleles; 0.0062%) in gnomAD (http://gnomad.broadinstitute.org/variant/1-160097482-G-A). This variant is interpreted as pathogenic. -

Familial hemiplegic migraine

Pathogenic:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 297 of the ATP1A2 protein (p.Ala297Thr). This variant is present in population databases (rs181618883, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ATP1A2-related conditions (PMID: 31737037; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430293). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Alternating hemiplegia of childhood 1

Pathogenic:1

Feb 05, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migraine, familial hemiplegic, 2;C3549447:Alternating hemiplegia of childhood 1

Uncertain:1

May 26, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing;provider interpretation

This 9 year old female with an intellectual disability was found to carry a missense variant in the ATP1A2 gene. Inheritance is unknown, as is paternal family history. She is non-dysmorphic, normocephalic, and does not have any congenital anomalies. At the date of report, the patient was not presenting with signs of migraines or hemiplegia. The variant is absent from population databases. It is a non-conservative substitution that occurs at a position that is conserved across species. In silico analysis predicts that the variant is probably damaging to protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.66

MVP

0.87

MPC

1.8

ClinPred

0.98

GERP RS

4.9

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.92

gMVP

0.99

Mutation Taster

=6/94

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over