1-160128761-C-T

Position:

• chr1-160128761-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000702.4(ATP1A2):​c.1127C>T​(p.Thr376Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T376R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.84

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-160128761-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204885.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.
• 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, 0.991
• PP5: Variant 1-160128761-C-T is Pathogenic according to our data. Variant chr1-160128761-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160128761-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-160128761-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.1127C>T	p.Thr376Met	missense_variant	9/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.236C>T	p.Thr79Met	missense_variant	2/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.1127C>T	p.Thr376Met	missense_variant	9/23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.1127C>T	p.Thr376Met	missense_variant	9/23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.257C>T	p.Thr86Met	missense_variant	2/16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.1230C>T		non_coding_transcript_exon_variant	9/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2024	Published functional studies demonstrate a damaging effect and show that this variant results in loss of function and affects sodium-potassium pump functioning (PMID: 18728015, 17952365); 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; This variant is associated with the following publications: (PMID: 16088919, 17952365, 28717674, 18184292, 18728015) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2019

The p.T376M pathogenic mutation (also known as c.1127C>T), located in coding exon 9 of the ATP1A2 gene, results from a C to T substitution at nucleotide position 1127. The threonine at codon 376 is replaced by methionine, an amino acid with similar properties. This mutation was identified in multiple affected individuals with familial hemiplegic migraine and was shown to segregate with disease in 3 families (Riant F et al. Hum. Mutat., 2005 Sep;26:281; Castro MJ et al. J. Hum. Genet., 2007 Oct;52:990-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Migraine, familial hemiplegic, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Familial hemiplegic migraine Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 16, 2019

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A2 protein function (PMID: 18728015). This variant has been observed to segregate with familial hemiplegic migraine in families (PMID: PMID: 16088919, 17952365). ClinVar contains an entry for this variant (Variation ID: 12930). This variant is present in population databases (rs121918620, ExAC 0.001%). This sequence change replaces threonine with methionine at codon 376 of the ATP1A2 protein (p.Thr376Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.94		Loss of methylation at K375 (P = 0.0308);Loss of methylation at K375 (P = 0.0308);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.75
gMVP		0.98

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: rs121918620; hg19: chr1-160098551; COSMIC: COSV100768285; COSMIC: COSV100768285;