rs1064797245

Variant names:

• chr19-41970540-G-A
• rs1064797245
• NM_152296.5:c.2266C>T
• ATP1A3 p.Arg756Cys

Your query was ambiguous. Multiple possible variants found:

• chr19-41970540-G-A
• chr19-41970540-G-T

GermlineCancer (beta)

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 15 classification points (ACMG Germline Pathogenicity v2019): 15P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Strong

The NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.03). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R756H: Pathogenic/Likely_pathogenic (ClinVar VariationId 161134, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 8.03
• Publications: 28 publications found

Genes affected

ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) 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 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ATP1A3 Gene-Disease associations (from GenCC):

• alternating hemiplegia of childhood 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ATP1A3-associated neurological disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, ClinGen
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• developmental and epileptic encephalopathy 99

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dystonia 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• encephalopathy, acute, infection-induced

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• alternating hemiplegia of childhood

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285505 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 15 points.

• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 6 pathogenic, 0 benign (OR vs. background: 65.0).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R756H: Pathogenic/Likely_pathogenic (ClinVar VariationId 161134, 2 stars)
• PP2: Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 9.135). ClinVar shows strong pathogenic missense enrichment: 152 P/LP and 24 B/LB missense entries (ratio 6.3×).
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (18/18 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_152296.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	NM_152296.5	MANE Select	c.2266C>T	p.Arg756Cys	missense splice_region	Exon 17 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.2305C>T	p.Arg769Cys	missense splice_region	Exon 17 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.2299C>T	p.Arg767Cys	missense splice_region	Exon 17 of 23	NP_001243142.1	P13637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.2266C>T	p.Arg756Cys	missense splice_region	Exon 17 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.2266C>T		splice_region non_coding_transcript_exon	Exon 17 of 25	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.2305C>T	p.Arg769Cys	missense splice_region	Exon 17 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
2	-	-	Alternating hemiplegia of childhood 2 (2)
2	-	-	ATP1A3-related disorder (2)
2	-	-	Dystonia 12 (3)
1	-	-	ATP1A3-associated neurological disorder (1)
1	-	-	Autosomal dominant ATP1A3-related disorders (1)
1	-	-	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (1)
1	-	-	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.4	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.72
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1064797245;

hg19: chr19-42474692;

COSMIC: COSV105875664;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar