1-160135460-C-G

Variant names:

• chr1-160135460-C-G
• rs139022921
• NM_000702.4:c.2142C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000702.4(ATP1A2):​c.2142C>G​(p.Asp714Glu) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D714D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.903

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 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000702.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.2142C>G	p.Asp714Glu	missense_variant	Exon 16 of 23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.1251C>G	p.Asp417Glu	missense_variant	Exon 9 of 16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2142C>G	p.Asp714Glu	missense_variant	Exon 16 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.2142C>G	p.Asp714Glu	missense_variant	Exon 16 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.1272C>G	p.Asp424Glu	missense_variant	Exon 9 of 16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.2245C>G		non_coding_transcript_exon_variant	Exon 16 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jun 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jan 09, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	6.5
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	4.3	H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.66	P;.
Vest4		0.81
MutPred		0.94		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		-7.0
Varity_R		0.37
gMVP		0.99

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: rs139022921; hg19: chr1-160105250;