rs121918613

Positions:

• chr1-160128667-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The ENST00000361216.8(ATP1A2):​c.1033A>G​(p.Thr345Ala) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 ENST00000361216.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.29

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 8 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 ENST00000361216.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A2. . Gene score misZ 4.7713 (greater than the threshold 3.09). Trascript score misZ 6.824 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.924
• PP5: Variant 1-160128667-A-G is Pathogenic according to our data. Variant chr1-160128667-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12923.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-160128667-A-G is described in Lovd as [Pathogenic]. Variant chr1-160128667-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.1033A>G	p.Thr345Ala	missense_variant	9/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.142A>G	p.Thr48Ala	missense_variant	2/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.1033A>G	p.Thr345Ala	missense_variant	9/23	1	NM_000702.4	ENSP00000354490	P1
ATP1A2	ENST00000392233.7	c.1033A>G	p.Thr345Ala	missense_variant	9/23	5		ENSP00000376066
ATP1A2	ENST00000447527.1	c.166A>G	p.Thr56Ala	missense_variant	2/16	2		ENSP00000411705
ATP1A2	ENST00000472488.5	n.1136A>G		non_coding_transcript_exon_variant	9/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Migraine, familial hemiplegic, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.76		Gain of MoRF binding (P = 0.1219);Gain of MoRF binding (P = 0.1219);
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.95

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: rs121918613; hg19: chr1-160098457;