rs17846715

Variant names:

• chr1-160135577-C-T
• rs17846715
• NM_000702.4:c.2259C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000702.4(ATP1A2):​c.2259C>T​(p.Ala753Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,000 control chromosomes in the GnomAD database, including 10,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (873 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10126 hom.)
• Consequence: ATP1A2 NM_000702.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.533
• Publications: 10 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP6: Variant 1-160135577-C-T is Benign according to our data. Variant chr1-160135577-C-T is described in ClinVar as Benign. ClinVar VariationId is 128481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.533 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 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.2259C>T	p.Ala753Ala	synonymous	Exon 16 of 23	NP_000693.1	P50993

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A2	ENST00000361216.8	TSL:1 MANE Select	c.2259C>T	p.Ala753Ala	synonymous	Exon 16 of 23	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.2283C>T	p.Ala761Ala	synonymous	Exon 16 of 23	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.2259C>T	p.Ala753Ala	synonymous	Exon 16 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14067 AN: 152048 Hom.: 871 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0621

Gnomad SAS AF: 0.0940

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0956

GnomAD2 exomes AF: 0.111 AC: 27911 AN: 251404 AF XY: 0.111

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0598

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.115 AC: 167607 AN: 1461834 Hom.: 10126 Cov.: 34 AF XY: 0.115 AC XY: 83387 AN XY: 727218

African (AFR) AF: 0.0168 AC: 561 AN: 33480

American (AMR) AF: 0.132 AC: 5899 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2858 AN: 26136

East Asian (EAS) AF: 0.0488 AC: 1936 AN: 39700

South Asian (SAS) AF: 0.107 AC: 9254 AN: 86254

European-Finnish (FIN) AF: 0.167 AC: 8936 AN: 53420

Middle Eastern (MID) AF: 0.0616 AC: 352 AN: 5716

European-Non Finnish (NFE) AF: 0.118 AC: 131397 AN: 1112010

Other (OTH) AF: 0.106 AC: 6414 AN: 60394

GnomAD4 genome AF: 0.0925 AC: 14076 AN: 152166 Hom.: 873 Cov.: 32 AF XY: 0.0949 AC XY: 7056 AN XY: 74390

African (AFR) AF: 0.0207 AC: 861 AN: 41552

American (AMR) AF: 0.117 AC: 1791 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3468

East Asian (EAS) AF: 0.0621 AC: 321 AN: 5172

South Asian (SAS) AF: 0.0937 AC: 451 AN: 4814

European-Finnish (FIN) AF: 0.166 AC: 1762 AN: 10590

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8206 AN: 67968

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.109 Hom.: 644

Bravo AF: 0.0830

Asia WGS AF: 0.0860 AC: 301 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.106

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Alternating hemiplegia of childhood 1 (2)
-	-	2	Migraine, familial hemiplegic, 2 (2)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy 98 (1)
-	-	1	Familial hemiplegic migraine (1)
-	-	1	Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.7
DANN	Benign	0.67
PhyloP100		0.53
Mutation Taster		=97/3	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: rs17846715; hg19: chr1-160105367;