chr1-160128767-C-A

Variant names:

• chr1-160128767-C-A
• rs28934002
• NM_000702.4:c.1133C>A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000702.4(ATP1A2):​c.1133C>A​(p.Thr378Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T378I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000702.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-160128767-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 392148.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.
• PP2: Missense variant in the ATP1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.7713 (above the threshold of 3.09). Trascript score misZ: 6.824 (above the threshold of 3.09). GenCC associations: The gene is linked to fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, alternating hemiplegia of childhood, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, familial or sporadic hemiplegic migraine, alternating hemiplegia of childhood 1, developmental and epileptic encephalopathy 98, migraine, familial hemiplegic, 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-160128767-C-A is Pathogenic according to our data. Variant chr1-160128767-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160128767-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.1133C>A	p.Thr378Asn	missense_variant	Exon 9 of 23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.242C>A	p.Thr81Asn	missense_variant	Exon 2 of 16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.1133C>A	p.Thr378Asn	missense_variant	Exon 9 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.1133C>A	p.Thr378Asn	missense_variant	Exon 9 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.263C>A	p.Thr88Asn	missense_variant	Exon 2 of 16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.1236C>A		non_coding_transcript_exon_variant	Exon 9 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 1 Pathogenic:2

Sep 16, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ATP1A2-related disorder Pathogenic:1

Nov 30, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP1A2 gene is constrained against missense variation (Z-score= 4.77), and missense variants are a common mechanism of disease (HGMD, ClinVar database; PMID: 34384358, 33711927). The c.1133C>A (p.Thr378Asn) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported in as a heterozygous change in patients with alternating hemiplegia (PMID: 15174025, 15286158) and familial hemiplegic migraine (PMID: 34384358). Functional studies indicate this variant may lead to reduced Na+/K+-ATPase activity (PMID: 34384358, 15286158). The c.1133C>A (p.Thr378Asn) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.1133C>A (p.Thr378Asn) is classified as Pathogenic. -

Familial hemiplegic migraine Pathogenic:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 378 of the ATP1A2 protein (p.Thr378Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alternating hemiplegia (PMID: 15174025, 15286158). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 15286158, 34384358). This variant disrupts the p.Thr378 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.96		Loss of ubiquitination at K375 (P = 0.1016);Loss of ubiquitination at K375 (P = 0.1016);
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.84
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs28934002; hg19: chr1-160098557;