1-160135160-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.1980C>T(p.Cys660Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,613,984 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 105 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 99 hom. )

Consequence

ATP1A2
NM_000702.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.25

Publications

4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
alternating hemiplegia of childhood 1
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
developmental and epileptic encephalopathy 98
Inheritance: AD 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=0.056).

BP6

Variant 1-160135160-C-T is Benign according to our data. Variant chr1-160135160-C-T is described in ClinVar as Benign. ClinVar VariationId is 128480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000702.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A2	NM_000702.4	MANE Select	c.1980C>T	p.Cys660Cys	synonymous	Exon 15 of 23	NP_000693.1	P50993

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP1A2	ENST00000361216.8	TSL:1 MANE Select	c.1980C>T	p.Cys660Cys	synonymous	Exon 15 of 23	ENSP00000354490.3	P50993
ATP1A2	ENST00000857225.1		c.2004C>T	p.Cys668Cys	synonymous	Exon 15 of 23	ENSP00000527284.1
ATP1A2	ENST00000969831.1		c.1980C>T	p.Cys660Cys	synonymous	Exon 15 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3113

AN:

151994

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0722

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00534

AC:

1330

AN:

249106

AF XY:

0.00393

show subpopulations

Gnomad AFR exome

AF:

0.0742

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000179

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00212

AC:

3095

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1359

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0757

AC:

2535

AN:

33478

American (AMR)

AF:

0.00315

AC:

141

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000980

AC:

109

AN:

1112006

Other (OTH)

AF:

0.00444

AC:

268

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

215

430

645

860

1075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0205

AC:

3113

AN:

152112

Hom.:

105

Cov.:

AF XY:

0.0199

AC XY:

1483

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0720

AC:

2986

AN:

41474

American (AMR)

AF:

0.00556

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68010

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

153

306

459

612

765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00864

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Migraine, familial hemiplegic, 2 (3)

Alternating hemiplegia of childhood 1 (2)

not specified (2)

Developmental and epileptic encephalopathy 98 (1)

Familial hemiplegic migraine (1)

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

1.1

(source)

DANN

Benign

0.66

PhyloP100

-1.3

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over