rs2295623

Positions:

• chr1-160127525-C-A

Variant summary

Our verdict is Benign. Variant got -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

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 -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
ATP1A2	NM_000702.4	c.749-27C>A		intron_variant		ENST00000361216.8	NP_000693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.749-27C>A		intron_variant		1	NM_000702.4	ENSP00000354490	P1
ATP1A2	ENST00000392233.7	c.749-27C>A		intron_variant		5		ENSP00000376066
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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

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
BranchPoint Hunter		2.0

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;