chr1-160136370-G-A

Position:

• chr1-160136370-G-A

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.2563G>A​(p.Gly855Arg) 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. 15/27 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G855E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.03

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 transmembrane_region Helical (size 22) in uniprot entity AT1A2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr1-160136570-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.988
• PP5: Variant 1-160136370-G-A is Pathogenic according to our data. Variant chr1-160136370-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 446871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160136370-G-A is described in Lovd as [Pathogenic]. Variant chr1-160136370-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.2563G>A	p.Gly855Arg	missense_variant, splice_region_variant	18/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.1672G>A	p.Gly558Arg	missense_variant, splice_region_variant	11/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2563G>A	p.Gly855Arg	missense_variant, splice_region_variant	18/23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.2563G>A	p.Gly855Arg	missense_variant, splice_region_variant	18/23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.1693G>A	p.Glu565Lys	missense_variant, splice_region_variant	11/16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.2666G>A		splice_region_variant, non_coding_transcript_exon_variant	18/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Migraine, familial hemiplegic, 2;C3549447:Alternating hemiplegia of childhood 1;C5562015:Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies;C5562017:Developmental and epileptic encephalopathy 98 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 21, 2021

- -

Familial hemiplegic migraine Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 19874388, 24921013). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 446871). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 19874388). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 855 of the ATP1A2 protein (p.Gly855Arg). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. -

Migraine, familial hemiplegic, 2;C3549447:Alternating hemiplegia of childhood 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 16, 2022

- -

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	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;.
Vest4		0.69
MutPred		0.95		Gain of methylation at G855 (P = 0.0308);Gain of methylation at G855 (P = 0.0308);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -40
DS_DL_spliceai		0.48		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553245857; hg19: chr1-160106160; COSMIC: COSV63404569; COSMIC: COSV63404569;