rs41288127

Variant names:

• chr1-160139998-C-T
• rs41288127
• NM_000702.4:c.3034+14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000702.4(ATP1A2):​c.3034+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,612,062 control chromosomes in the GnomAD database, including 14,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1360 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13548 hom.)
• Consequence: ATP1A2 NM_000702.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.134
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-160139998-C-T is Benign according to our data. Variant chr1-160139998-C-T is described in ClinVar as Benign. ClinVar VariationId is 256764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.3034+14C>T		intron_variant	Intron 22 of 22	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.2143+14C>T		intron_variant	Intron 15 of 15		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.3034+14C>T		intron_variant	Intron 22 of 22	1	NM_000702.4	ENSP00000354490.3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19735 AN: 151930 Hom.: 1358 Cov.: 31

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.130 AC: 32641 AN: 250404 AF XY: 0.129

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0608

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.133 AC: 194626 AN: 1460014 Hom.: 13548 Cov.: 33 AF XY: 0.133 AC XY: 96623 AN XY: 726416

African (AFR) AF: 0.109 AC: 3643 AN: 33466

American (AMR) AF: 0.142 AC: 6366 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2773 AN: 26130

East Asian (EAS) AF: 0.0493 AC: 1957 AN: 39694

South Asian (SAS) AF: 0.117 AC: 10055 AN: 86244

European-Finnish (FIN) AF: 0.190 AC: 9927 AN: 52372

Middle Eastern (MID) AF: 0.0746 AC: 430 AN: 5766

European-Non Finnish (NFE) AF: 0.137 AC: 152009 AN: 1111264

Other (OTH) AF: 0.124 AC: 7466 AN: 60354

GnomAD4 genome AF: 0.130 AC: 19745 AN: 152048 Hom.: 1360 Cov.: 31 AF XY: 0.131 AC XY: 9748 AN XY: 74324

African (AFR) AF: 0.112 AC: 4657 AN: 41470

American (AMR) AF: 0.135 AC: 2062 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 359 AN: 3466

East Asian (EAS) AF: 0.0624 AC: 323 AN: 5174

South Asian (SAS) AF: 0.104 AC: 499 AN: 4818

European-Finnish (FIN) AF: 0.185 AC: 1951 AN: 10556

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9514 AN: 67974

Other (OTH) AF: 0.125 AC: 265 AN: 2114

Alfa AF: 0.142 Hom.: 305

Bravo AF: 0.122

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 27% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 25. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Migraine, familial hemiplegic, 2 Benign:2

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. -

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

- -

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	-0.84
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41288127; hg19: chr1-160109788;