1-160132270-C-T

Variant names:

• chr1-160132270-C-T
• rs6686067
• NM_000702.4:c.1827+1673C>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.1827+1673C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 151,880 control chromosomes in the GnomAD database, including 56,725 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 0.86 (56725 hom., cov: 28)
• Consequence: ATP1A2 NM_000702.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.567
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A2	NM_000702.4	MANE Select	c.1827+1673C>T		intron	N/A	NP_000693.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A2	ENST00000361216.8	TSL:1 MANE Select	c.1827+1673C>T		intron	N/A	ENSP00000354490.3
	ATP1A2	ENST00000392233.7	TSL:5	c.1827+1673C>T		intron	N/A	ENSP00000376066.3
	ATP1A2	ENST00000447527.1	TSL:2	c.957+1673C>T		intron	N/A	ENSP00000411705.1

Frequencies

GnomAD3 genomes AF: 0.862 AC: 130763 AN: 151762 Hom.: 56684 Cov.: 28

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.867

Gnomad OTH AF: 0.839

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

GnomAD4 genome AF: 0.862 AC: 130857 AN: 151880 Hom.: 56725 Cov.: 28 AF XY: 0.857 AC XY: 63617 AN XY: 74196

African (AFR) AF: 0.921 AC: 38143 AN: 41424

American (AMR) AF: 0.736 AC: 11226 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2870 AN: 3468

East Asian (EAS) AF: 0.675 AC: 3475 AN: 5146

South Asian (SAS) AF: 0.851 AC: 4061 AN: 4774

European-Finnish (FIN) AF: 0.893 AC: 9433 AN: 10564

Middle Eastern (MID) AF: 0.849 AC: 248 AN: 292

European-Non Finnish (NFE) AF: 0.867 AC: 58865 AN: 67926

Other (OTH) AF: 0.833 AC: 1760 AN: 2112

Alfa AF: 0.837 Hom.: 13298

Bravo AF: 0.850

Asia WGS AF: 0.766 AC: 2666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.14
DANN	Benign	0.59
PhyloP100		-0.57
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: rs6686067; hg19: chr1-160102060;