ATP2B2

protein-coding

ATPase plasma membrane Ca2+ transporting 2, the group of ATPases Ca2+ transporting|MicroRNA protein coding host genes

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 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001001331.4

Inheritance

ClinVar variants

P:68U:314B:185

Top phenotype

Deafness, autosomal dominant 82

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr3:10,324,023-10,708,007

External References & Databases

Ensembl (ENSG00000157087)

Transcript & Mutation Effects

hg38 • Region Span ~384.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal dominant 82STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030719

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: ClinGen

ATP2B2 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2018 (Smits et al., PMID: 30535804). This condition is characterized by early-onset/congenital hearing loss, which ranges in severity and is often progressive. 8 variants (nonsense, frameshift, splicing), many of which were de novo, that have been reported in at least 26 probands in 4 publications (PMIDs: 30535804, 33105617, 33111345, 36194208) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (2 mouse models and functional alteration evidence; PMIDs: 9668038, 20826782). Mutant mouse models show significant hearing loss in both homozygous and heterozygous mutants. Other features seen in the mutants include lack of otoconia, structural ear anomalies, and impaired calcium homeostasis. Functional alteration evidence in Chinese Hamster Ovary cells shows impaired calcium homeostasis in the mutants. In summary, there is definitive evidence supporting the relationship between ATP2B2 and autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 06/18/2025 (SOP Version 11).

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

hearing loss, autosomal dominant 82DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030719

Submitter: Ambry Genetics

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

hearing loss, autosomal dominant 82STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030719

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 82AD

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 30535804

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP2B2 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 461

not specifiedTotal: 201

ATP2B2-related disorderTotal: 95

Hearing loss, autosomal dominant 82Total: 29

Neurodevelopmental disorderTotal: 5

Autosomal recessive nonsyndromic hearing loss 12Total: 4

Epileptic encephalopathyTotal: 2

Autosomal dominant nonsyndromic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001001331.4. 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			4 clinvar	149 clinvar	14 clinvar	167
missense	3 clinvar	9 clinvar	301 clinvar	19 clinvar	2 clinvar	334
nonsense	9 clinvar	8 clinvar				17
start loss			1 clinvar			1
frameshift	17 clinvar	10 clinvar	1 clinvar			28
splice donor/acceptor (+/-2bp)	1 clinvar	11 clinvar	7 clinvar	1 clinvar		20
Total	30	38	314	169	16	567

Highest pathogenic variant AF is 0.000003120526

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001001331.4	RefSeq	NP_001001331.1	22	MANE Select
ENST00000360273.7	Ensembl	ENSP00000353414.2	22	MANE Select
NM_001330611.3	RefSeq	NP_001317540.1	20	Standard
NM_001353564.1	RefSeq	NP_001340493.1	19	Standard

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)
Salivary secretion - Homo sapiens (human)

Biological Process

calcium ion transport
cellular calcium ion homeostasis
sensory perception of sound
neuron differentiation
ion transmembrane transport

Molecular Function

calcium-transporting ATPase activity
protein binding
calmodulin binding
ATP binding
PDZ domain binding

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
cell junction
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360273
Coding exons: 22
Length: 384010
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.55	431	791	0.545	0.0000554	8189
Missense (PolyPhen)		216	466.62	0.46291		4759
Synonymous	-0.802	366	347	1.05	0.0000282	2469
Loss of Function	6.33	3	52.5	0.0572	0.00000254	614

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	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: 0.180

Intolerance Scores

LoFtool: 0.00400
RVIS EVS: -1.94
RVIS percentile EVS: 1.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.744

Gene Damage Prediction

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