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: 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), ClinGen, Ambry Genetics, G2P
• 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, Labcorp Genetics (formerly Invitae), G2P
• 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.

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.3034+14C>T		intron	N/A	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.3034+14C>T		intron	N/A	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.3058+14C>T		intron	N/A	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.3031+17C>T		intron	N/A	ENSP00000639890.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41288127;

hg19: chr1-160109788;