rs796052277

Variant names:

• chr1-160135992-T-A
• rs796052277
• NM_000702.4:c.2438T>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000702.4(ATP1A2):​c.2438T>A​(p.Met813Lys) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense, splice_region
• Scores: Splicing: ADA: 0.7317
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 8.00

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 17 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, 6 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, 0.942
• PP5: Variant 1-160135992-T-A is Pathogenic according to our data. Variant chr1-160135992-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.2438T>A	p.Met813Lys	missense_variant, splice_region_variant	Exon 17 of 23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.1547T>A	p.Met516Lys	missense_variant, splice_region_variant	Exon 10 of 16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2438T>A	p.Met813Lys	missense_variant, splice_region_variant	Exon 17 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.2438T>A	p.Met813Lys	missense_variant, splice_region_variant	Exon 17 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.1568T>A	p.Met523Lys	missense_variant, splice_region_variant	Exon 10 of 16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.2541T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 98 Pathogenic:1

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 09, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Met813Lys (ATG>AAG): c.2438 T>A in exon 17 of the ATP1A2 gene (NM_000702.3). The Met813Lys missense change has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a uncharged, non-polar Methionine residue is replaced by a positively charged, polar Lysine residue. Met813Lys alters a conserved position in the M6 transmembrane domain of the ATP1A2 protein and several in-silico algorithms predict it may be damaging to the structure/function of the protein. The Met813Lys variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Migraine, familial hemiplegic, 2 Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Likely pathogenicity based on finding it de novo in a 2-year-old male with developmental delay, seizure disorder, alternating hemiplegic migraine, and left hemiparesis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.47	P;.
Vest4		0.86
MutPred		0.77		Gain of ubiquitination at M813 (P = 0.0203);Gain of ubiquitination at M813 (P = 0.0203);
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Benign	0.63
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: rs796052277; hg19: chr1-160105782;