ATP2A2

ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, the group of ATPases Ca2+ transporting

Basic information

Region (hg38): 12:110280755-110351093

Previous symbols: [ "ATP2B", "DAR" ]

Links

ENSG00000174437 ∙ NCBI:488 ∙ OMIM:108740 ∙ HGNC:812 ∙ Uniprot:P16615 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Darier disease (Definitive), mode of inheritance: AD
• acrokeratosis verruciformis (Strong), mode of inheritance: AD
• Darier disease (Strong), mode of inheritance: AD
• Darier disease (Strong), mode of inheritance: AD
• Darier disease (Supportive), mode of inheritance: AD
• acrokeratosis verruciformis (Supportive), mode of inheritance: AD
• acrokeratosis verruciformis (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Darier-White disease; Acrokeratosis verruciformis (Hopf disease)	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Dermatologic	921905; 1619075; 10441324; 10080178; 10441323; 11121153; 12542527; 12925205; 14675181; 22004489; 22035154; 22329366; 22814319; 22909361
In Darier-White disease, oral retinoids may be beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP2A2 gene.

• not provided (130 variants)
• Keratosis follicularis (100 variants)
• Acrokeratosis verruciformis of Hopf (20 variants)
• Inborn genetic diseases (16 variants)
• not specified (11 variants)
• Keratosis follicularis;Acrokeratosis verruciformis of Hopf (3 variants)
• Acrokeratosis verruciformis of Hopf;Keratosis follicularis (2 variants)
• Darier disease, acral hemorrhagic type (1 variants)
• ATP2A2-related condition (1 variants)
• Darier disease, segmental (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP2A2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	22	15	41
missense	11	13	40	5	2	71
nonsense	2					2
start loss	2					2
frameshift	8	5				13
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	4				5
splice region			1	4	5	10
non coding			35	13	18	66
Total	24	22	80	40	35

Variants in ATP2A2

This is a list of pathogenic ClinVar variants found in the ATP2A2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-110281247-A-G		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281278-C-G		Keratosis follicularis	Uncertain significance (Apr 27, 2017)
12-110281290-T-C		Keratosis follicularis	Benign (Jan 12, 2018)
12-110281308-C-T		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281314-C-T		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281321-G-C		Keratosis follicularis	Uncertain significance (Jan 12, 2018)
12-110281332-G-A		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281387-C-G		Keratosis follicularis	Benign (Jan 13, 2018)
12-110281399-C-T		Keratosis follicularis	Uncertain significance (Aug 30, 2017)
12-110281455-C-A		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281466-G-A		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281479-G-T		Keratosis follicularis	Uncertain significance (Jan 12, 2018)
12-110281516-G-C		Keratosis follicularis	Benign (Jan 13, 2018)
12-110281550-G-A		Keratosis follicularis	Benign (Jan 13, 2018)
12-110281584-C-T		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281623-C-T		Keratosis follicularis	Uncertain significance (Jan 12, 2018)
12-110281625-C-G		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281715-C-T		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281753-G-C		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281756-G-A		Keratosis follicularis	Uncertain significance (Jan 13, 2018)
12-110281775-C-T		Keratosis follicularis	Benign (Jan 13, 2018)
12-110281780-C-G		Keratosis follicularis • not specified • Acrokeratosis verruciformis of Hopf • Acrokeratosis verruciformis of Hopf;Keratosis follicularis	Benign/Likely benign (Jun 01, 2023)
12-110281790-A-G			Pathogenic (Jun 20, 2023)
12-110281790-A-T			Pathogenic (Apr 21, 2016)
12-110281801-G-T			Benign (Oct 12, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP2A2	protein_coding	protein_coding	ENST00000539276	20	70338

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000551	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.88	246	575	0.428	0.0000339	6824
Missense in Polyphen		40	228.79	0.17484		2656
Synonymous	-0.127	226	224	1.01	0.0000151	2094
Loss of Function	5.62	6	48.1	0.125	0.00000274	558

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Isoform 2 is involved in the regulation of the contraction/relaxation cycle (PubMed:16402920). Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64 which is critical for the TNFSF11- induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca (2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca (2+) signaling cascades that promote osteoclast differentiation and activation (By similarity). {ECO:0000250|UniProtKB:O55143, ECO:0000269|PubMed:16402920}.
• Disease: DISEASE: Acrokeratosis verruciformis (AKV) [MIM:101900]: A localized disorder of keratinization, which is inherited as an autosomal dominant trait. Its onset is early in life with multiple flat-topped, flesh-colored papules on the hands and feet, punctate keratoses on the palms and soles, with varying degrees of nail involvement. The histopathology shows a distinctive pattern of epidermal features with hyperkeratosis, hypergranulosis and acanthosis together with papillomatosis. These changes are frequently associated with circumscribed elevations of the epidermis that are said to resemble church spires. There are no features of dyskeratosis or acantholysis, the typical findings in lesions of Darier disease. {ECO:0000269|PubMed:12542527}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Darier disease (DD) [MIM:124200]: A skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp and forehead), palmoplantar pits and distinctive nail abnormalities. It is due to loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Patients with mild disease may have no more than a few scattered keratotic papules or subtle nail changes, whereas those with severe disease are handicapped by widespread malodorous keratotic plaques. Some patients present with hemorrhage into acantholytic vesicles on the palms and dorsal aspects of the fingers which gives rise to black macules. In a few families affected by Darier disease, neuropsychiatric abnormalities such as mild mental retardation, schizophrenia, bipolar disorder and epilepsy have been reported. Stress, UV exposure, heat, sweat, friction and oral contraception exacerbate disease symptoms. Clinical variants of Darier disease include hypertrophic, vesicobullous, hypopigmented, cornifying, zosteriform or linear, acute and comedonal subtypes. Comedonal Darier disease is characterized by the coexistence of acne-like comedonal lesions with typical Darier hyperkeratotic papules on light-exposed areas. At histopathologic level, comedonal Darier disease differs from classic Darier disease in the prominent follicular involvement and the presence of greatly elongated dermal villi. {ECO:0000269|PubMed:10080178, ECO:0000269|PubMed:10441323, ECO:0000269|PubMed:10441324, ECO:0000269|PubMed:10441325, ECO:0000269|PubMed:19995371, ECO:0000269|PubMed:28035777}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cardiac muscle contraction - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics;Thyroid hormone signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;miR-targeted genes in epithelium - TarBase;miR-targeted genes in leukocytes - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;miR-targeted genes in squamous cell - TarBase;Alzheimers Disease;Arrhythmogenic Right Ventricular Cardiomyopathy;Endothelin Pathways;Myometrial Relaxation and Contraction Pathways;Calcium Regulation in the Cardiac Cell;nfat and hypertrophy of the heart ;Ion channel transport;Purine metabolism;Ion homeostasis;Transport of small molecules;Cardiac conduction;Muscle contraction;Ion transport by P-type ATPases;Hemostasis;Reduction of cytosolic Ca++ levels;Platelet calcium homeostasis;Platelet homeostasis (Consensus)

Recessive Scores

• pRec: 0.461

Intolerance Scores

• loftool: 0.0220
• rvis_EVS: -1.6
• rvis_percentile_EVS: 3.04

Haploinsufficiency Scores

• pHI: 0.266
• hipred: Y
• hipred_score: 0.685
• ghis: 0.636

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.989

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Atp2a2
• Phenotype: neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; digestive/alimentary phenotype; muscle phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: atp2a2a
• Affected structure: atrium
• Phenotype tag: abnormal
• Phenotype quality: decreased contractility

Gene ontology

• Biological process: regulation of the force of heart contraction;skeletal muscle contraction;cellular calcium ion homeostasis;ER-nucleus signaling pathway;organelle organization;cell adhesion;epidermis development;positive regulation of heart rate;regulation of cardiac muscle contraction by calcium ion signaling;transition between fast and slow fiber;cardiac muscle hypertrophy in response to stress;endoplasmic reticulum calcium ion homeostasis;positive regulation of endoplasmic reticulum calcium ion concentration;response to lipopolysaccharide;T-tubule organization;ion transmembrane transport;cellular response to oxidative stress;cellular response to heat;response to endoplasmic reticulum stress;negative regulation of heart contraction;relaxation of cardiac muscle;sarcoplasmic reticulum calcium ion transport;calcium ion transmembrane transport;regulation of cardiac muscle cell membrane potential;regulation of cardiac muscle cell action potential involved in regulation of contraction;ATP hydrolysis coupled cation transmembrane transport;proton transmembrane transport;regulation of calcium ion-dependent exocytosis of neurotransmitter;calcium ion transport from cytosol to endoplasmic reticulum;regulation of cardiac conduction;calcium ion import into sarcoplasmic reticulum
• Cellular component: nucleoplasm;endoplasmic reticulum;endoplasmic reticulum membrane;integral component of plasma membrane;vesicle membrane;membrane;sarcoplasmic reticulum;platelet dense tubular network membrane;extrinsic component of cytoplasmic side of plasma membrane;protein-containing complex;sarcoplasmic reticulum membrane;perinuclear region of cytoplasm;apical ectoplasmic specialization;ribbon synapse;plasma membrane bounded cell projection
• Molecular function: calcium-transporting ATPase activity;calcium ion binding;protein binding;ATP binding;proton-exporting ATPase activity, phosphorylative mechanism;enzyme binding;lutropin-choriogonadotropic hormone receptor binding;S100 protein binding;calcium-transporting ATPase activity involved in regulation of cardiac muscle cell membrane potential