rs781687346

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1

The NM_000702.4(ATP1A2):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,601,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ATP1A2
NM_000702.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.41

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.10315934).

BP6

Variant 1-160115869-G-A is Benign according to our data. Variant chr1-160115869-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204902.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000108 (157/1448958) while in subpopulation NFE AF = 0.000135 (149/1106218). AF 95% confidence interval is 0.000117. There are 0 homozygotes in GnomAdExome4. There are 68 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4 link	c.8G>A	p.Arg3His	missense_variant	Exon 1 of 23	ENST00000361216.8	NP_000693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ATP1A2	ENST00000361216.8 link	c.8G>A	p.Arg3His	missense_variant	Exon 1 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7 link	c.8G>A	p.Arg3His	missense_variant	Exon 1 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000472488.5 link	n.111G>A		non_coding_transcript_exon_variant	Exon 1 of 20	2
ATP1A2	ENST00000478587.1 link	n.107G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000483

AC:

AN:

227940

AF XY:

0.0000654

show subpopulations

Gnomad AFR exome

AF:

0.0000705

Gnomad AMR exome

AF:

0.0000935

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000583

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000487

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

157

AN:

1448958

Hom.:

Cov.:

AF XY:

0.0000946

AC XY:

AN XY:

719128

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33356

American (AMR)

AF:

0.0000468

AC:

AN:

42730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

39326

South Asian (SAS)

AF:

0.0000480

AC:

AN:

83342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000135

AC:

149

AN:

1106218

Other (OTH)

AF:

0.0000167

AC:

AN:

59972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41540

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jan 12, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATP1A2 c.8G>A (p.Arg3His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 227940 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP1A2 causing Alternating Hemiplegia Of Childhood 1, allowing no conclusion about variant significance. c.8G>A has been reported in the literature in at-least one individual affected with epilepsy (Coll_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Alternating Hemiplegia Of Childhood 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29261713). ClinVar contains an entry for this variant (Variation ID: 204902). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Migraine, familial hemiplegic, 2

Uncertain:1

Jul 06, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hemiplegic migraine

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3 of the ATP1A2 protein (p.Arg3His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204902). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATP1A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Feb 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.032

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.90

L;.

PhyloP100

2.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.45

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.53

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.82

P;.

Vest4

0.29

MVP

0.84

MPC

1.0

ClinPred

0.031

GERP RS

4.7

PromoterAI

0.025

Neutral

(source)

Varity_R

0.12

gMVP

0.45

Mutation Taster

=72/28

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over