CA8

protein-coding

carbonic anhydrase 8, the group of Carbonic anhydrases

Gene summary

The protein encoded by this gene was initially named CA-related protein because of sequence similarity to other known carbonic anhydrase genes. However, the gene product lacks carbonic anhydrase activity (i.e., the reversible hydration of carbon dioxide). The gene product continues to carry a carbonic anhydrase designation based on clear sequence identity to other members of the carbonic anhydrase gene family. The absence of CA8 gene transcription in the cerebellum of the lurcher mutant in mice with a neurologic defect suggests an important role for this acatalytic form. Mutations in this gene are associated with cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CMARQ3). Polymorphisms in this gene are associated with osteoporosis, and overexpression of this gene in osteosarcoma cells suggests an oncogenic role. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Previous symbols:

CALS

MANE transcript

NM_004056.6

Inheritance

ClinVar variants

P:11U:34B:14

Top phenotype

Spinocerebellar ataxia, autosomal recessive 34

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr8:60,185,412-60,281,400

External References & Databases

Ensembl (ENSG00000178538)

Transcript & Mutation Effects

hg38 • Region Span ~96.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013188

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar ataxiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0000437

Submitter: ClinGen

*CA8* was first reported in relation to autosomal recessive cerebellar ataxia in 2009 (Turkmen et al., PMID: 19461874). *CA8*-related cerebellar ataxia is characterized by features of cerebellar ataxia such as wide-based or quadrupedal gait, intention tremor, dysarthria, cerebellar atrophy, and developmental delay with or without cognitive delay (PMIDs: 19461874, 21812104, 21937992, 27217339, 31693170, 32808436). Six variants (5 missense and 1 truncating) that have been reported in 12 individuals (6 probands) in 6 publications (PMIDs: 19461874, 21812104, 21937992, 27217339, 31693170, 32808436) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. The ataxic mouse model 'Rigoletto' (rig) carries a 19-bp deletion in *Car8*, the mouse homolog of *CA8*. Studies of cerebellar Purkinje cells in these mice showed decreased spontaneous excitatory transmission with a reportedly lower number of functional synapses. Mutants also showed abnormalities of the extension of climbing fibers to distal Purkinje cell dendrites, of parallel fibers and dendritic spines (including free spines that did not form normal synapses), and multiple synaptic varicosities. The authors concluded that Car8 plays a critical role in synaptogenesis and/or maintenance of proper synaptic morphology and function in the cerebellum (PMID: 17376701). Expression studies also indicated specific expression of CAR8 in cerebellar Purkinje cells and minimal to absent expression in the spinal cord and cerebral cortex (PMIDs: 16118194, 31693170). In summary, there is moderate evidence supporting the relationship between *CA8* and autosomal recessive cerebellar ataxia. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 16, 2024 (SOP Version 10).

cerebellar ataxia, intellectual disability, and dysequilibriumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009133

Submitter: Orphanet

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013188

Submitter: G2P

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 34AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19461874; 21937992

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CA8 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 30

not providedTotal: 25

not specifiedTotal: 11

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3Total: 11

CA8-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004056.6. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	10 clinvar	3 clinvar	14
missense	4 clinvar	2 clinvar	32 clinvar		1 clinvar	39
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	5	6	34	10	4	59

Highest pathogenic variant AF is 0.0000047884005

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004056.6	RefSeq	NP_004047.3	8	MANE Select
ENST00000317995.5	Ensembl	ENSP00000314407.4	8	MANE Select
NM_001321837.2	RefSeq	NP_001308766.1	8	Standard
NM_001321838.2	RefSeq	NP_001308767.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ca8	Danio rerio	Structure: neuron Quality: apoptotic abnormal

Gene / Model

Organism

Observed Phenotype

ca8

Danio rerio

Structure: neuron

Quality: apoptotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nitrogen metabolism - Homo sapiens (human)

Biological Process

phosphatidylinositol-mediated signaling

Molecular Function

carbonate dehydratase activity
protein binding
zinc ion binding

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000317995
Coding exons: 8
Length: 94066
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.24	115	159	0.723	0.00000809	1880
Missense (PolyPhen)		22	48.089	0.45748		582
Synonymous	-0.0688	63	62.3	1.01	0.00000332	554
Loss of Function	2.64	7	19.6	0.357	0.00000107	207

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Does not have a carbonic anhydrase catalytic activity.;
Disease: DISEASE: Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CMARQ3) [MIM:613227]: A congenital cerebellar ataxia associated with dysarthia, quadrupedal gait and mental retardation. {ECO:0000269|PubMed:19461874}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.136

Intolerance Scores

LoFtool: 0.514
RVIS EVS: -0.01
RVIS percentile EVS: 53.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.910

Gene Damage Prediction

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