1-160130474-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000702.4(ATP1A2):c.1704C>T(p.Phe568Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,614,164 control chromosomes in the GnomAD database, including 749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 106 hom., cov: 32)

Exomes 𝑓: 0.027 ( 643 hom. )

Consequence

ATP1A2
NM_000702.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.54

Publications

6 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.128).

BP6

Variant 1-160130474-C-T is Benign according to our data. Variant chr1-160130474-C-T is described in ClinVar as Benign. ClinVar VariationId is 128479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.54 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4 link	c.1704C>T	p.Phe568Phe	synonymous_variant	Exon 13 of 23	ENST00000361216.8	NP_000693.1	P50993A0A0S2Z3W6
ATP1A2	XM_047421286.1 link	c.813C>T	p.Phe271Phe	synonymous_variant	Exon 6 of 16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP1A2	ENST00000361216.8 link	c.1704C>T	p.Phe568Phe	synonymous_variant	Exon 13 of 23	1	NM_000702.4	ENSP00000354490.3	P50993
ATP1A2	ENST00000392233.7 link	c.1704C>T	p.Phe568Phe	synonymous_variant	Exon 13 of 23	5		ENSP00000376066.3	B1AKY9
ATP1A2	ENST00000447527.1 link	c.834C>T	p.Phe278Phe	synonymous_variant	Exon 6 of 16	2		ENSP00000411705.1	H0Y7C1
ATP1A2	ENST00000472488.5 link	n.1807C>T		non_coding_transcript_exon_variant	Exon 13 of 20	2

Frequencies

GnomAD3 genomes

AF:

0.0348

AC:

5291

AN:

152156

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0260

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.0353

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0318

Gnomad OTH

AF:

0.0421

GnomAD2 exomes

AF:

0.0287

AC:

7211

AN:

251478

AF XY:

0.0284

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0533

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0335

Gnomad OTH exome

AF:

0.0415

GnomAD4 exome

AF:

0.0273

AC:

39864

AN:

1461890

Hom.:

643

Cov.:

AF XY:

0.0274

AC XY:

19934

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0467

AC:

1563

AN:

33480

American (AMR)

AF:

0.0180

AC:

803

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0515

AC:

1346

AN:

26136

East Asian (EAS)

AF:

0.000655

AC:

AN:

39700

South Asian (SAS)

AF:

0.0158

AC:

1361

AN:

86258

European-Finnish (FIN)

AF:

0.0369

AC:

1973

AN:

53420

Middle Eastern (MID)

AF:

0.0600

AC:

346

AN:

5768

European-Non Finnish (NFE)

AF:

0.0277

AC:

30751

AN:

1112008

Other (OTH)

AF:

0.0281

AC:

1695

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2798

5595

8393

11190

13988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1096

2192

3288

4384

5480

<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:

0.0348

AC:

5292

AN:

152274

Hom.:

106

Cov.:

AF XY:

0.0345

AC XY:

2572

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0486

AC:

2020

AN:

41550

American (AMR)

AF:

0.0260

AC:

398

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5182

South Asian (SAS)

AF:

0.0126

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0353

AC:

374

AN:

10600

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0319

AC:

2167

AN:

68018

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

274

547

821

1094

1368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0338

Hom.:

196

Bravo

AF:

0.0355

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0344

EpiControl

AF:

0.0362

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 12, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migraine, familial hemiplegic, 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alternating hemiplegia of childhood 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 21, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy 98

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial hemiplegic migraine

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.94

(source)

DANN

Benign

0.69

PhyloP100

-2.5

Mutation Taster

=99/1

polymorphism (auto)

(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