GeneBe

CA2

protein-coding

carbonic anhydrase 2, the group of Carbonic anhydrases

Gene summary

The protein encoded by this gene is one of several isozymes of carbonic anhydrase, which catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

MANE transcript

NM_000067.3

Inheritance

AR

ClinVar variants

P:23U:85B:37

Top phenotype

Osteopetrosis, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr8:85,463,968-85,481,493

External References & Databases

Ensembl (ENSG00000104267)NCBI Gene (760)OMIM (611492)HGNC:1373GenCCUniProt (P00918)AlphaFoldClinVar (CA2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~17.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009818

Submitter: G2P

autosomal recessive osteopetrosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009818

Submitter: ClinGen

*CA2* was first reported in relation to autosomal recessive osteopetrosis 3 in 1991 (Venta et al. 1991, PMID: 1928091). Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis (OPT), renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications. It is also known as Carbonic anhydrase 2 deficiency, Guibaud-Vainsel syndrome, Marble brain disease, Mixed RTA, and RTA type 3. Eleven unique variants (missense, nonsense, frameshift, splice-site) that have been reported in 8 probands in 8 publications (PMIDs: 1928091, 1542674, 7627193, 19556665, 27848944, 33555497, 28509178, 37662627) are included in this curation. Variants in this gene segregated in 4 additional family members (PMIDs: 1542674, 28509178). More proband is reported in the literature but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is supported by biochemical function study, expression data, and a mouse model replicating the phenotype (PMIDs: 8200964, 6405388, 16396925, 3126501, 18175028). In summary, there is definitive evidence to support the relationship between *CA2* and autosomal recessive osteopetrosis 3. 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 Skeletal Disorders GCEP on the meeting date June 10th, 2024 (SOP Version 10).

autosomal recessive osteopetrosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009818

Submitter: Genomics England PanelApp

autosomal recessive osteopetrosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009818

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive osteopetrosis 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009818

Submitter: Orphanet

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal recessive 3AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Musculoskeletal; Renal

Rationale: Identification and treatment of renal tubular acidosis may be beneficial; Awareness of multi-organ system complications of osteopetrosis may allow surveillance and prompt management

Refs: 5041390; 7386510; 7312081; 3925334; 3081869; 2107079; 1928091; 1301935; 1542674; 8127074; 7627193; 8834238; 9143915; 12566520Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CA2 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 125
Osteopetrosis with renal tubular acidosisTotal: 79
Inborn genetic diseasesTotal: 28
CA2-related disorderTotal: 11
not specifiedTotal: 6
CARBONIC ANHYDRASE II VARIANTTotal: 3
Neurodevelopmental delayTotal: 2
OsteopetrosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000067.3. 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
3
clinvar
33
clinvar
 36
missense
3
clinvar
1
clinvar
77
clinvar
3
clinvar
1
clinvar
 85
nonsense
3
clinvar
4
clinvar
1
clinvar
 8
start loss
1
clinvar
 1
frameshift
2
clinvar
4
clinvar
1
clinvar
 7
splice donor/acceptor (+/-2bp)
2
clinvar
3
clinvar
3
clinvar
 8
Total101385361145

Highest pathogenic variant AF is 0.000018592038

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000067.3RefSeqNP_000058.17MANE Select
ENST00000285379.10EnsemblENSP00000285379.47MANE Select
NM_001293675.2RefSeqNP_001280604.15Standard
ENST00000520127.5EnsemblENSP00000428443.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cahzDanio rerio

Structure: respiratory gaseous exchange

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Bile secretion - Homo sapiens (human)
  • Gastric acid secretion - Homo sapiens (human)
  • Proximal tubule bicarbonate reclamation - Homo sapiens (human)
  • Collecting duct acid secretion - Homo sapiens (human)
  • Pancreatic secretion - Homo sapiens (human)

Biological Process

  • kidney development
  • morphogenesis of an epithelium
  • response to pH
  • response to zinc ion
  • carbon dioxide transport

Molecular Function

  • arylesterase activity
  • carbonate dehydratase activity
  • protein binding
  • zinc ion binding

Cellular Component

  • cytoplasm
  • cytosol
  • plasma membrane
  • microvillus
  • basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000285379
Coding exons
7
Length
17642
Individuals with no LoFs
125729
Homozygous LoFs
0
Heterozygous LoFs
19
Defined
125748
p
0.0000756
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.3591281400.9140.000007511709
Missense (PolyPhen)4257.1590.73479713
Synonymous0.4344953.00.9240.00000299488
Loss of Function0.6151012.30.8115.26e-7153

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian0.000160.00016rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate exchange activity of SLC26A6. {ECO:0000250, ECO:0000269|PubMed:10550681, ECO:0000269|PubMed:11831900, ECO:0000269|PubMed:15990874}.;
Disease
DISEASE: Osteopetrosis, autosomal recessive 3 (OPTB3) [MIM:259730]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation. {ECO:0000269|PubMed:15300855, ECO:0000269|PubMed:1542674, ECO:0000269|PubMed:1928091, ECO:0000269|PubMed:8834238, ECO:0000269|PubMed:9143915}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.372

Intolerance Scores

LoFtool
0.466
RVIS EVS
-0.14
RVIS percentile EVS
43.29

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.913

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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