ATP2B1

protein-coding

ATPase plasma membrane Ca2+ transporting 1, the group of ATPases Ca2+ transporting

Gene summary

The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 1. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001366521.1

Inheritance

AD, AR

ClinVar variants

P:53U:231B:20

Top phenotype

Intellectual developmental disorder, autosomal dominant 66

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr12:89,588,049-89,709,366

External References & Databases

Ensembl (ENSG00000070961)

Transcript & Mutation Effects

hg38 • Region Span ~121.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 66MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030891

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 66STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030891

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 66STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030891

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 66LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030891

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 66MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030891

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 66AD

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: General

Rationale: Among other findings, the condition can involve congenital heart anomalies, and awareness may allow prompt diagnosis and management

Refs: 35358416

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP2B1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 129

Inborn genetic diseasesTotal: 93

Intellectual developmental disorder, autosomal dominant 66Total: 60

ATP2B1-related disorderTotal: 21

not specifiedTotal: 18

Neurodevelopmental disorderTotal: 14

Isolated Pierre-Robin syndromeTotal: 2

Neurodevelopmental delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366521.1. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	9 clinvar	4 clinvar	15
missense	1 clinvar	12 clinvar	219 clinvar	6 clinvar	1 clinvar	239
nonsense	7 clinvar	7 clinvar				14
start loss			1 clinvar			1
frameshift	7 clinvar	12 clinvar	3 clinvar			22
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	6 clinvar			13
Total	16	37	231	15	5	304

Highest pathogenic variant AF is 0.0000030987344

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 87 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366521.1	RefSeq	NP_001353450.1	20	MANE Select
ENST00000428670.8	Ensembl	ENSP00000392043.3	20	MANE Select
NM_001001323.2	RefSeq	NP_001001323.1	21	Standard
NM_001366520.1	RefSeq	NP_001353449.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atp2b1a	Danio rerio	Structure: neuromast hair cell Quality: has fewer parts of type abnormal

Gene / Model

Organism

Observed Phenotype

atp2b1a

Danio rerio

Structure: neuromast hair cell

Quality: has fewer parts of type

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aldosterone synthesis and secretion - Homo sapiens (human)
Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)
Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human)

Biological Process

neural retina development
cellular calcium ion homeostasis
brain development
aging
response to cold

Molecular Function

calcium-transporting ATPase activity
protein binding
calmodulin binding
ATP binding
calcium ion transmembrane transporter activity

Cellular Component

nucleus
plasma membrane
integral component of plasma membrane
cytoplasmic side of plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428670
Coding exons: 20
Length: 121250
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125737
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.29	271	651	0.416	0.0000332	7990
Missense (PolyPhen)		86	309.61	0.27777		3785
Synonymous	1.05	202	222	0.910	0.0000114	2366
Loss of Function	6.83	1	56.3	0.0178	0.00000305	719

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell.;

Recessive Scores

pRec: 0.230

Intolerance Scores

LoFtool: 0.00551
RVIS EVS: -1.02
RVIS percentile EVS: 7.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.814

Gene Damage Prediction

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