NM_152296.5:c.2266_2268delCGCinsTTG

Variant names:

• chr19-41970538-GCG-CAA
• NM_152296.5:c.2266_2268delCGCinsTTG
• ATP1A3 p.Arg756Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO7_SupportingO8_Supporting

The NM_152296.5(ATP1A3):c.2266_2268delCGCinsTTG (p.Arg756Leu) variant causes a missense, splice region change. The gene ATP1A3 is a known oncogene (CancerMine: 1 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.03). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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)

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• ATP1A3-associated neurological disorder

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer does not indicate an oncogenic effect; O6 not met via missense path; Splice-region variant — splicing algorithms predict an impact on splicing; supports O6
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 6 pathogenic, 0 benign (OR vs. background: 65.0); No cancerhotspots.org splice hotspot hit at this position
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 9.14 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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.2266_2268delCGCinsTTG p.Arg756Leu	missensesplice_region	N/A	Prot: NP_689509.1 UniProt:
	ATP1A3 NM_001256214.2		c.2305_2307delCGCinsTTG p.Arg769Leu	missensesplice_region	N/A	Prot: NP_001243143.1 UniProt:
	ATP1A3 NM_001256213.2		c.2299_2301delCGCinsTTG p.Arg767Leu	missensesplice_region	N/A	Prot: NP_001243142.1 UniProt:

ATP1A3 NM_152296.5

MANE Select

HGVSc / HGVSpc.2266_2268delCGCinsTTGp.Arg756Leu

Exon rankN/A

missensesplice_region

Prot: NP_689509.1UniProt: P13637-1

ATP1A3 NM_001256214.2

HGVSc / HGVSpc.2305_2307delCGCinsTTGp.Arg769Leu

Exon rankN/A

missensesplice_region

Prot: NP_001243143.1UniProt: P13637-3

ATP1A3 NM_001256213.2

HGVSc / HGVSpc.2299_2301delCGCinsTTGp.Arg767Leu

Exon rankN/A

missensesplice_region

Prot: NP_001243142.1UniProt: P13637-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATP1A3 ENST00000648268.1	MANE Select	c.2266_2268delCGCinsTTG p.Arg756Leu	missensesplice_region	N/A	Prot: ENSP00000498113.1 UniProt:
	ENSG00000285505 ENST00000644613.1		n.2266_2268delCGCinsTTG	splice_regionnon_coding_transcript_exon	Exon 17 of 25	Prot: ENSP00000494711.1 UniProt:
	ATP1A3 ENST00000545399.6	TSL:2	c.2305_2307delCGCinsTTG p.Arg769Leu	missensesplice_region	N/A	Prot: ENSP00000444688.1 UniProt:

ATP1A3 ENST00000648268.1

MANE Select

HGVSc / HGVSpc.2266_2268delCGCinsTTGp.Arg756Leu

Exon rankN/A

missensesplice_region

Prot: ENSP00000498113.1UniProt: P13637-1

ENSG00000285505 ENST00000644613.1

HGVSc / HGVSpn.2266_2268delCGCinsTTG

Exon rankExon 17 of 25

splice_regionnon_coding_transcript_exon

Prot: ENSP00000494711.1UniProt: A0A2R8YEY8

ATP1A3 ENST00000545399.6

TSL:2

HGVSc / HGVSpc.2305_2307delCGCinsTTGp.Arg769Leu

Exon rankN/A

missensesplice_region

Prot: ENSP00000444688.1UniProt: P13637-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr19-42474690;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar