rs12410866

Variant names:

• chr1-160139013-C-T
• rs12410866
• NM_000702.4:c.2841-627C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000702.4(ATP1A2):​c.2841-627C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 152,246 control chromosomes in the GnomAD database, including 1,051 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1051 hom., cov: 32)
• Consequence: ATP1A2 NM_000702.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.293
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.2841-627C>T		intron_variant	Intron 20 of 22	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.1950-627C>T		intron_variant	Intron 13 of 15		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2841-627C>T		intron_variant	Intron 20 of 22	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.2841-627C>T		intron_variant	Intron 20 of 22	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.1920-627C>T		intron_variant	Intron 13 of 15	2		ENSP00000411705.1
ATP1A2	ENST00000463989.1	n.177-627C>T		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15365 AN: 152128 Hom.: 1049 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.101 AC: 15373 AN: 152246 Hom.: 1051 Cov.: 32 AF XY: 0.103 AC XY: 7681 AN XY: 74436

African (AFR) AF: 0.0232 AC: 965 AN: 41550

American (AMR) AF: 0.125 AC: 1907 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3472

East Asian (EAS) AF: 0.0632 AC: 328 AN: 5186

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4822

European-Finnish (FIN) AF: 0.185 AC: 1964 AN: 10588

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9063 AN: 68006

Other (OTH) AF: 0.106 AC: 224 AN: 2116

Alfa AF: 0.118 Hom.: 2115

Bravo AF: 0.0902

Asia WGS AF: 0.0870 AC: 304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.93
DANN	Benign	0.36
PhyloP100		-0.29
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: rs12410866; hg19: chr1-160108803;