GeneBe

ATP2A1

protein-coding

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

Gene summary

This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

Previous symbols:
  • ATP2A

MANE transcript

NM_004320.6

Inheritance

AR, AD

ClinVar variants

P:70U:419B:228

Top phenotype

Brody disease

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr16:28,878,405-28,904,466

External References & Databases

Ensembl (ENSG00000196296)NCBI Gene (487)OMIM (108730)HGNC:811GenCCUniProt (O14983)AlphaFoldClinVar (ATP2A1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~26.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brody myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010977

Submitter: Labcorp Genetics (formerly Invitae)

Brody myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010977

Submitter: Genomics England PanelApp

Brody myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010977

Submitter: Orphanet

Brody myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010977

Submitter: Ambry Genetics

Brody myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010977

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Brody diseaseAR

Manifestation: Musculoskeletal

Intervention: Musculoskeletal

Rationale: 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

Refs: 1405485; 8040329; 8841193; 9367679; 10914677; 20142766Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP2A1 variants in ClinVar

7 Conditions Cataloged
Brody myopathyTotal: 786
not providedTotal: 169
Inborn genetic diseasesTotal: 102
not specifiedTotal: 65
ATP2A1-related disorderTotal: 36
Skeletal muscle channelopathyTotal: 2
See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004320.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
10
clinvar
212
clinvar
4
clinvar
 226
missense
2
clinvar
2
clinvar
403
clinvar
11
clinvar
1
clinvar
 419
nonsense
14
clinvar
8
clinvar
 22
start loss
1
clinvar
 1
frameshift
17
clinvar
11
clinvar
1
clinvar
 29
splice donor/acceptor (+/-2bp)
2
clinvar
14
clinvar
4
clinvar
 20
Total35354192235717

Highest pathogenic variant AF is 0.00024192978

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004320.6RefSeqNP_004311.122MANE Select
ENST00000395503.9EnsemblENSP00000378879.522MANE Select
NM_001286075.2RefSeqNP_001273004.118Standard
NM_173201.5RefSeqNP_775293.122Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
atp2a1Danio rerio

Structure: fast muscle cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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

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

Molecular Function

  • calcium-transporting ATPase activity
  • calcium ion binding
  • protein binding
  • ATP binding
  • proton-exporting ATPase activity, phosphorylative mechanism

Cellular Component

  • mitochondrion
  • endoplasmic reticulum membrane
  • integral component of membrane
  • sarcoplasmic reticulum
  • platelet dense tubular network membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000357084
Coding exons
22
Length
26105
Individuals with no LoFs
125635
Homozygous LoFs
0
Heterozygous LoFs
113
Defined
125748
p
0.000449
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.544966020.8240.00004106501
Missense (PolyPhen)255320.130.796543514
Synonymous0.03532502510.9970.00001802070
Loss of Function2.503048.80.6140.00000299523

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00037rare
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish00.0absent
East Asian0.000330.00033rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000610.00061rare
South Asian0.000690.00069rare
Other0.000330.00033rare

dbNSFP Gene Annotations

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.;

Intolerance Scores

LoFtool
0.0805
RVIS EVS
-1.39
RVIS percentile EVS
4.27

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.769

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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