rs2295623

chr1-160127525-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★).

• 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, single submitter B:1
• Conservation: PhyloP100: 0.787

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: 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 ClinVar as [Benign]. Clinvar id is 670905.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-160127525-C-A is described in Lovd as [Benign]. Variant chr1-160127525-C-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
ATP1A2	NM_000702.4	c.749-27C>A		intron_variant		ENST00000361216.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A2	ENST00000361216.8	c.749-27C>A		intron_variant		1	NM_000702.4	P1
ATP1A2	ENST00000392233.7	c.749-27C>A		intron_variant		5
ATP1A2	ENST00000472488.5	n.852-27C>A		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0931 AC: 23138 AN: 248542 Hom.: 1217 AF XY: 0.0940 AC XY: 12643 AN XY: 134540

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 SAS exome AF: 0.0639

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

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.0768

Gnomad4 ASJ exome AF: 0.0739

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.0643

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.0996

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

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.0870

Gnomad4 ASJ AF: 0.0723

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.0598

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0808

Alfa AF: 0.0949 Hom.: 146

Bravo AF: 0.0816

Asia WGS AF: 0.113 AC: 391 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.8
Dann	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs2295623; hg19: chr1-160097315; COSMIC: COSV63405044; COSMIC: COSV63405044;