rs2217342

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_152296.5(ATP1A3):c.666T>G(p.Thr222Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 1,614,130 control chromosomes in the GnomAD database, including 660,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T222T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.92 ( 64869 hom., cov: 33)

Exomes 𝑓: 0.90 ( 595802 hom. )

Consequence

ATP1A3
NM_152296.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -4.07

Publications

38 publications found

Variant links:

Genes affected

ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) 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 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ATP1A3 Gene-Disease associations (from GenCC):

alternating hemiplegia of childhood 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
ATP1A3-associated neurological disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
developmental and epileptic encephalopathy 99
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
dystonia 12
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
encephalopathy, acute, infection-induced
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
alternating hemiplegia of childhood
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ATP1A3 links:

ENSG00000285505 (HGNC:):

ENSG00000285505 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 19-41985364-A-C is Benign according to our data. Variant chr19-41985364-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5 link	c.666T>G	p.Thr222Thr	synonymous_variant	Exon 7 of 23	ENST00000648268.1	NP_689509.1	P13637-1Q53ES0
ATP1A3	NM_001256214.2 link	c.705T>G	p.Thr235Thr	synonymous_variant	Exon 7 of 23		NP_001243143.1	P13637-3Q53ES0
ATP1A3	NM_001256213.2 link	c.699T>G	p.Thr233Thr	synonymous_variant	Exon 7 of 23		NP_001243142.1	P13637-2Q53ES0
ATP1A3	XM_047438862.1 link	c.576T>G	p.Thr192Thr	synonymous_variant	Exon 7 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1 link	c.666T>G	p.Thr222Thr	synonymous_variant	Exon 7 of 23		NM_152296.5	ENSP00000498113.1		P13637-1
ENSG00000285505	ENST00000644613.1 link	n.666T>G		non_coding_transcript_exon_variant	Exon 7 of 25			ENSP00000494711.1		A0A2R8YEY8

Frequencies

GnomAD3 genomes

AF:

0.922

AC:

140238

AN:

152138

Hom.:

64804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.981

Gnomad AMI

AF:

0.931

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.863

Gnomad EAS

AF:

0.876

Gnomad SAS

AF:

0.821

Gnomad FIN

AF:

0.942

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.907

Gnomad OTH

AF:

0.887

GnomAD2 exomes

AF:

0.890

AC:

223667

AN:

251436

AF XY:

0.885

show subpopulations

Gnomad AFR exome

AF:

0.985

Gnomad AMR exome

AF:

0.858

Gnomad ASJ exome

AF:

0.865

Gnomad EAS exome

AF:

0.870

Gnomad FIN exome

AF:

0.938

Gnomad NFE exome

AF:

0.902

Gnomad OTH exome

AF:

0.886

GnomAD4 exome

AF:

0.902

AC:

1318948

AN:

1461874

Hom.:

595802

Cov.:

AF XY:

0.899

AC XY:

653920

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.984

AC:

32954

AN:

33480

American (AMR)

AF:

0.858

AC:

38355

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.863

AC:

22553

AN:

26136

East Asian (EAS)

AF:

0.878

AC:

34853

AN:

39700

South Asian (SAS)

AF:

0.819

AC:

70658

AN:

86256

European-Finnish (FIN)

AF:

0.939

AC:

50158

AN:

53420

Middle Eastern (MID)

AF:

0.795

AC:

4587

AN:

5768

European-Non Finnish (NFE)

AF:

0.909

AC:

1010704

AN:

1111996

Other (OTH)

AF:

0.896

AC:

54126

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

8435

16869

25304

33738

42173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21482

42964

64446

85928

107410

<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:

0.922

AC:

140367

AN:

152256

Hom.:

64869

Cov.:

AF XY:

0.921

AC XY:

68525

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.981

AC:

40758

AN:

41550

American (AMR)

AF:

0.883

AC:

13502

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.863

AC:

2995

AN:

3472

East Asian (EAS)

AF:

0.875

AC:

4528

AN:

5172

South Asian (SAS)

AF:

0.822

AC:

3970

AN:

4828

European-Finnish (FIN)

AF:

0.942

AC:

10000

AN:

10618

Middle Eastern (MID)

AF:

0.796

AC:

234

AN:

294

European-Non Finnish (NFE)

AF:

0.907

AC:

61653

AN:

68006

Other (OTH)

AF:

0.889

AC:

1878

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

569

1138

1706

2275

2844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.903

Hom.:

103293

Bravo

AF:

0.920

EpiCase

AF:

0.894

EpiControl

AF:

0.897

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 91. Only high quality variants are reported. -

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dystonia 12

Benign:3

Jan 13, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alternating hemiplegia of childhood 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.96

CADD

Benign

0.012

(source)

DANN

Benign

0.19

PhyloP100

-4.1

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