NM_000702.4:c.749-27C>A

Variant names:

• chr1-160127525-C-A
• rs2295623
• NM_000702.4:c.749-27C>A

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.749-27C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,650 control chromosomes in the GnomAD database, including 9,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.083 (649 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8555 hom.)
• Consequence: ATP1A2 NM_000702.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.787
• Publications: 11 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-160127525-C-A is Benign according to our data. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160127525-C-A is described in CliVar as Benign. Clinvar id is 670905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.749-27C>A		intron_variant	Intron 7 of 22	ENST00000361216.8	NP_000693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.749-27C>A		intron_variant	Intron 7 of 22	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.749-27C>A		intron_variant	Intron 7 of 22	5		ENSP00000376066.3
ATP1A2	ENST00000472488.5	n.852-27C>A		intron_variant	Intron 7 of 19	2
ATP1A2	ENST00000447527.1	c.-149C>A		upstream_gene_variant		2		ENSP00000411705.1

Frequencies

GnomAD3 genomes AF: 0.0829 AC: 12617 AN: 152124 Hom.: 654 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0591

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0812

GnomAD2 exomes AF: 0.0931 AC: 23138 AN: 248542 AF XY: 0.0940

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.0728

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0968

GnomAD4 exome AF: 0.106 AC: 154674 AN: 1461408 Hom.: 8555 Cov.: 33 AF XY: 0.104 AC XY: 75813 AN XY: 726980

African (AFR) AF: 0.0188 AC: 630 AN: 33472

American (AMR) AF: 0.0768 AC: 3432 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0739 AC: 1930 AN: 26130

East Asian (EAS) AF: 0.127 AC: 5042 AN: 39700

South Asian (SAS) AF: 0.0643 AC: 5547 AN: 86226

European-Finnish (FIN) AF: 0.108 AC: 5732 AN: 53278

Middle Eastern (MID) AF: 0.0677 AC: 380 AN: 5612

European-Non Finnish (NFE) AF: 0.113 AC: 125967 AN: 1111904

Other (OTH) AF: 0.0996 AC: 6014 AN: 60384

GnomAD4 genome AF: 0.0828 AC: 12607 AN: 152242 Hom.: 649 Cov.: 32 AF XY: 0.0816 AC XY: 6070 AN XY: 74428

African (AFR) AF: 0.0223 AC: 926 AN: 41560

American (AMR) AF: 0.0870 AC: 1331 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 251 AN: 3470

East Asian (EAS) AF: 0.141 AC: 729 AN: 5174

South Asian (SAS) AF: 0.0598 AC: 288 AN: 4818

European-Finnish (FIN) AF: 0.107 AC: 1129 AN: 10594

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7638 AN: 68008

Other (OTH) AF: 0.0808 AC: 171 AN: 2116

Alfa AF: 0.0929 Hom.: 146

Bravo AF: 0.0816

Asia WGS AF: 0.113 AC: 391 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.79
PhyloP100		0.79
BranchPoint Hunter		2.0
PromoterAI		0.0096	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2295623; hg19: chr1-160097315; COSMIC: COSV63405044; COSMIC: COSV63405044;