1-160121226-G-A

Position:

chr1-160121226-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_000702.4(ATP1A2):c.152G>A(p.Arg51His) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,614,222 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. R51C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ATP1A2
NM_000702.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.81

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:

ATP1A2 (HGNC:):

ATP1A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.21470454).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000274 (401/1461868) while in subpopulation NFE AF= 0.000339 (377/1112006). AF 95% confidence interval is 0.00031. There are 0 homozygotes in gnomad4_exome. There are 193 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4 linkuse as main transcript	c.152G>A	p.Arg51His	missense_variant	3/23	ENST00000361216.8	NP_000693.1	P50993A0A0S2Z3W6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ATP1A2	ENST00000361216.8 linkuse as main transcript	c.152G>A	p.Arg51His	missense_variant	3/23	1	NM_000702.4	ENSP00000354490.3	P50993
ATP1A2	ENST00000392233.7 linkuse as main transcript	c.152G>A	p.Arg51His	missense_variant	3/23	5		ENSP00000376066.3	B1AKY9
ATP1A2	ENST00000472488.5 linkuse as main transcript	n.255G>A		non_coding_transcript_exon_variant	3/20	2
ATP1A2	ENST00000478587.1 linkuse as main transcript	n.432G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251478

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000274

AC:

401

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

193

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000339

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000112

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2016	A variant of uncertain significance has been identified in the ATP1A2 gene. The R51H variant has been reported in association with migraine without aura; however, functional studies showed no significant differences between this variant and the wild type protein (Swarts et al., 2013). The R51H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R51H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2024	Variant summary: ATP1A2 c.152G>A (p.Arg51His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251478 control chromosomes (gnomAD). c.152G>A has been reported in the literature in a family with migraine without aura (Swarts_2013). This report does not provide unequivocal conclusions about association of the variant with Familial Hemiplegic Migraine. At least one publication reports experimental evidence evaluating an impact on protein function (Swarts_2013). These results showed no damaging effect of this variant. The following publication has been ascertained in the context of this evaluation (PMID: 23954377). ClinVar contains an entry for this variant (Variation ID: 372793). Based on the evidence outlined above, the variant was classified as uncertain significance. -

ATP1A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

The ATP1A2 c.152G>A variant is predicted to result in the amino acid substitution p.Arg51His. This variant has been reported in a three-generation Portuguese family with migraine without aura, however functional analysis of this variant showed results similar to wildtype (Swarts et al. 2013. PubMed ID: 23954377). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial hemiplegic migraine

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 51 of the ATP1A2 protein (p.Arg51His). This variant is present in population databases (rs144106169, gnomAD 0.02%). This missense change has been observed in individual(s) with migraine without aura (PMID: 23954377). ClinVar contains an entry for this variant (Variation ID: 372793). 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 not expected to disrupt ATP1A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP1A2 function (PMID: 23954377). 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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.079

T;T

Polyphen

0.0080

B;.

Vest4

0.45

MVP

0.75

MPC

0.93

ClinPred

0.081

GERP RS

4.6

Varity_R

0.15

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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