1-160129007-C-G

Variant names:

• chr1-160129007-C-G
• rs121918618
• NM_000702.4:c.1244C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000702.4(ATP1A2):​c.1244C>G​(p.Thr415Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T415M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-160129007-C-T is described in Lovd as [Pathogenic].
• 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.1244C>G	p.Thr415Arg	missense_variant	Exon 10 of 23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.353C>G	p.Thr118Arg	missense_variant	Exon 3 of 16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.1244C>G	p.Thr415Arg	missense_variant	Exon 10 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.1244C>G	p.Thr415Arg	missense_variant	Exon 10 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.374C>G	p.Thr125Arg	missense_variant	Exon 3 of 16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.1347C>G		non_coding_transcript_exon_variant	Exon 10 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemiplegic migraine Uncertain:1

Oct 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 not expected to disrupt ATP1A2 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 415 of the ATP1A2 protein (p.Thr415Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.96	L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.54		Gain of MoRF binding (P = 0.0156);Gain of MoRF binding (P = 0.0156);
MVP		0.90
MPC		1.9
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.70
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918618; hg19: chr1-160098797;