1-160128731-G-C

Variant names:

• chr1-160128731-G-C
• rs1057518514
• NM_000702.4:c.1097G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000702.4(ATP1A2):​c.1097G>C​(p.Gly366Ala) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G366D) 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 P:1 U:1
• Conservation: PhyloP100: 9.92
• Publications: 0 publications found

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]

ATP1A2 Gene-Disease associations (from GenCC):

• hemiplegic migraine-developmental and epileptic encephalopathy spectrum

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• migraine, familial hemiplegic, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• alternating hemiplegia of childhood 1

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• developmental and epileptic encephalopathy 98

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• alternating hemiplegia of childhood

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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, 7 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 chr1-160128730-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 493055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 developmental and epileptic encephalopathy 98, fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, migraine, familial hemiplegic, 2, alternating hemiplegia of childhood, alternating hemiplegia of childhood 1, familial or sporadic hemiplegic migraine, hemiplegic migraine-developmental and epileptic encephalopathy spectrum.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.1097G>C	p.Gly366Ala	missense_variant	Exon 9 of 23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.206G>C	p.Gly69Ala	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.1097G>C	p.Gly366Ala	missense_variant	Exon 9 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.1097G>C	p.Gly366Ala	missense_variant	Exon 9 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.227G>C	p.Gly76Ala	missense_variant	Exon 2 of 16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.1200G>C		non_coding_transcript_exon_variant	Exon 9 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 98 Pathogenic:1

Nov 10, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Dec 01, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the ATP1A2 gene. The G366A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G366A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (V362E, T364M, T368K) have been reported in the Human Gene Mutation Database in association with hemiplegic migraine (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the G366A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.6	L;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.84		Gain of catalytic residue at G366 (P = 0.1306);Gain of catalytic residue at G366 (P = 0.1306);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
gMVP		1.0
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs1057518514; hg19: chr1-160098521;