chr1-160130114-G-A

Position:

chr1-160130114-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_ModerateBS1BS2

The NM_000702.4(ATP1A2):c.1474G>A(p.Glu492Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,204 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 2 hom. )

Consequence

ATP1A2
NM_000702.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: 1.43

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A2. . Gene score misZ 4.7713 (greater than the threshold 3.09). Trascript score misZ 6.824 (greater than threshold 3.09). GenCC has associacion of gene with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, alternating hemiplegia of childhood, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, familial or sporadic hemiplegic migraine, alternating hemiplegia of childhood 1, developmental and epileptic encephalopathy 98, migraine, familial hemiplegic, 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.106758386).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000505 (77/152328) while in subpopulation NFE AF= 0.000838 (57/68030). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4 linkuse as main transcript	c.1474G>A	p.Glu492Lys	missense_variant	12/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1 linkuse as main transcript	c.583G>A	p.Glu195Lys	missense_variant	5/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ATP1A2	ENST00000361216.8 linkuse as main transcript	c.1474G>A	p.Glu492Lys	missense_variant	12/23	1	NM_000702.4	ENSP00000354490	P1
ATP1A2	ENST00000392233.7 linkuse as main transcript	c.1474G>A	p.Glu492Lys	missense_variant	12/23	5		ENSP00000376066
ATP1A2	ENST00000447527.1 linkuse as main transcript	c.607G>A	p.Glu203Lys	missense_variant	5/16	2		ENSP00000411705
ATP1A2	ENST00000472488.5 linkuse as main transcript	n.1577G>A		non_coding_transcript_exon_variant	12/20	2

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.000838

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000442

AC:

111

AN:

251174

Hom.:

AF XY:

0.000479

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000766

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000707

AC:

1033

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

509

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000872

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000505

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000904

Hom.:

Bravo

AF:

0.000676

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2024	Published in vitro functional studies suggest this variant results in partial loss of function due to reduced cell survival when transfected into HeLa cells (PMID: 18056581); Reported previously in a five-year-old male with hemiplegic migraine and his mother who had a history of migraines with aura but no hemiplegic attacks (PMID: 18056581); Reported in both affected individuals and healthy controls in a case-control study of patients with migraines (PMID: 36044383); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18957371, 34426522, 35982159, 18184292, 37234784, 33057194, 36044383, 18056581) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 07, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant is statistically more frequent in migraine-affected individuals than in the general population and/or healthy controls, suggesting in may be a risk factor for migraines. This variant has been identified in at least one individual with familial hemiplegic migraine. Assessment of experimental evidence suggests this variant results in abnormal protein function, although it shows a milder decrease in function than other known pathogenic variants. (PMID:18056581) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2021	- -

ATP1A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2024

The ATP1A2 c.1474G>A variant is predicted to result in the amino acid substitution p.Glu492Lys. This variant was reported in an individual with hemiplegic migraines and also in his mother who presented with migraines lacking hemiplegia. In vitro studies indicated that this variant may partially impact protein function (de Vries et al. 2007. PubMed ID: 18056581). However, this variant is reported on 0.081% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is significantly more common than any established pathogenic variant in this gene. Additionally, this variant was not statistically more prevalent in affected individuals compared to presumably asymptomatic controls (Markel et al. 2022. PubMed ID: 36044383). Although we suspect c.1474G>A (p.Glu492Lys) may be benign, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Migraine, familial hemiplegic, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hemiplegic migraine

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Alternating hemiplegia of childhood 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

-0.23

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.33

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0010

B;B

Vest4

0.73

MVP

0.98

MPC

0.85

ClinPred

0.024

GERP RS

3.7

Varity_R

0.14

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over