ATP2A1

ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1, the group of ATPases Ca2+ transporting

Basic information

Region (hg38): 16:28878404-28904466

Previous symbols: [ "ATP2A" ]

Links

ENSG00000196296 ∙ NCBI:487 ∙ OMIM:108730 ∙ HGNC:811 ∙ Uniprot:O14983 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Brody myopathy (Strong), mode of inheritance: AR
• Brody myopathy (Strong), mode of inheritance: AR
• Brody myopathy (Strong), mode of inheritance: AR
• Brody myopathy (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brody disease	AR	Musculoskeletal	Individuals typically present with exercise-induced muscle relaxation impairment, with, stiffening, cramps, and muscle pain, and medical management (eg, with dantrolene or verapamil) has been described as beneficial in some individuals	Musculoskeletal	1405485; 8040329; 8841193; 9367679; 10914677; 20142766

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP2A1 gene.

• Brody myopathy (661 variants)
• not provided (145 variants)
• not specified (44 variants)
• Inborn genetic diseases (29 variants)
• ATP2A1-related condition (3 variants)
• See cases (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP2A1 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			8	145	3	156
missense			332	1	3	336
nonsense	15	5				20
start loss			1			1
frameshift	9	3	1			13
inframe indel			3			3
splice donor/acceptor (+/-2bp)		13				13
splice region			13	21	2	36
non coding			11	96	32	139
Total	24	21	356	242	38

Highest pathogenic variant AF is 0.0000329

Variants in ATP2A1

This is a list of pathogenic ClinVar variants found in the ATP2A1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-28878650-C-T		Brody myopathy • not specified	Benign (Jan 12, 2018)
16-28878657-C-T		Brody myopathy	Uncertain significance (Jan 13, 2018)
16-28878660-G-A		not specified • Brody myopathy	Likely benign (Jan 13, 2018)
16-28878665-G-A		not specified	Likely benign (Jan 08, 2018)
16-28878670-C-T			Uncertain significance (Feb 10, 2021)
16-28878672-A-G		Brody myopathy	Uncertain significance (Aug 04, 2022)
16-28878675-G-A		Brody myopathy	Uncertain significance (May 24, 2022)
16-28878677-G-A		Brody myopathy	Likely benign (May 23, 2023)
16-28878680-C-T		Brody myopathy	Likely benign (May 09, 2023)
16-28878712-C-A		Brody myopathy	Uncertain significance (Jan 12, 2018)
16-28878715-A-G		Brody myopathy	Uncertain significance (Jun 18, 2022)
16-28878722-GGTGA-G		Brody myopathy	Pathogenic (Nov 13, 2023)
16-28878726-A-G		Brody myopathy	Uncertain significance (Sep 01, 2021)
16-28878729-G-A		Brody myopathy	Uncertain significance (May 23, 2022)
16-28878737-G-A		Brody myopathy	Likely benign (Dec 02, 2022)
16-28878749-G-A		Brody myopathy	Uncertain significance (Jan 13, 2018)
16-28878752-C-G		Brody myopathy	Uncertain significance (Nov 27, 2023)
16-28878759-A-C		Brody myopathy	Uncertain significance (Sep 24, 2021)
16-28878763-G-A		Brody myopathy	Uncertain significance (Oct 25, 2022)
16-28878769-T-A		Brody myopathy	Uncertain significance (Dec 09, 2021)
16-28878771-G-T		Brody myopathy • ATP2A1-related disorder	Conflicting classifications of pathogenicity (Feb 15, 2024)
16-28878780-G-A		Brody myopathy • Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
16-28878785-C-T		not specified	Likely benign (May 23, 2016)
16-28878787-A-G		Brody myopathy	Uncertain significance (Nov 25, 2021)
16-28878789-G-A		Brody myopathy	Uncertain significance (Sep 07, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP2A1	protein_coding	protein_coding	ENST00000357084	22	26105

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.54e-14	0.981	125635	0	113	125748	0.000449

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.54	496	602	0.824	0.0000410	6501
Missense in Polyphen		255	320.13	0.79654		3514
Synonymous	0.0353	250	251	0.997	0.0000180	2070
Loss of Function	2.50	30	48.8	0.614	0.00000299	523

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000601	0.000600
Ashkenazi Jewish	0.00	0.00
East Asian	0.000329	0.000326
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000609	0.000607
Middle Eastern	0.000329	0.000326
South Asian	0.000686	0.000686
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key regulator of striated muscle performance by acting as the major Ca(2+) ATPase responsible for the reuptake of cytosolic Ca(2+) into the sarcoplasmic reticulum. Catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Contributes to calcium sequestration involved in muscular excitation/contraction. {ECO:0000250|UniProtKB:Q8R429}.
• Disease: DISEASE: Brody myopathy (BRM) [MIM:601003]: A disorder of muscle function that is characterized by painless muscle cramping and exercise-induced impairment of muscle relaxation. {ECO:0000269|PubMed:10914677}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Alzheimer,s disease - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Antiarrhythmic Pathway, Pharmacodynamics;Alzheimers Disease;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)

Intolerance Scores

• loftool: 0.0805
• rvis_EVS: -1.39
• rvis_percentile_EVS: 4.27

Haploinsufficiency Scores

• pHI: 0.783
• hipred: Y
• hipred_score: 0.773
• ghis: 0.621

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.769

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atp2a1
• 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; homeostasis/metabolism phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: atp2a1
• Affected structure: fast muscle cell
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: calcium ion transport;cellular calcium ion homeostasis;apoptotic mitochondrial changes;positive regulation of fast-twitch skeletal muscle fiber contraction;positive regulation of endoplasmic reticulum calcium ion concentration;negative regulation of endoplasmic reticulum calcium ion concentration;ion transmembrane transport;response to endoplasmic reticulum stress;positive regulation of mitochondrial calcium ion concentration;maintenance of mitochondrion location;intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress;calcium ion import;calcium ion transmembrane transport;relaxation of skeletal muscle;ATP hydrolysis coupled cation transmembrane transport;proton transmembrane transport;regulation of cardiac conduction
• Cellular component: mitochondrion;endoplasmic reticulum membrane;integral component of membrane;sarcoplasmic reticulum;platelet dense tubular network membrane;sarcoplasmic reticulum membrane;calcium channel complex
• Molecular function: calcium-transporting ATPase activity;calcium ion binding;protein binding;ATP binding;proton-exporting ATPase activity, phosphorylative mechanism;protein homodimerization activity