CA5A

protein-coding

carbonic anhydrase 5A, the group of Carbonic anhydrases

Gene summary

Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA VA is localized in the mitochondria and expressed primarily in the liver. It may play an important role in ureagenesis and gluconeogenesis. CA5A gene maps to chromosome 16q24.3 and an unprocessed pseudogene has been assigned to 16p12-p11.2. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_001739.2

Inheritance

ClinVar variants

P:13U:104B:73

Top phenotype

Carbonic anhydrase VA deficiency

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr16:87,881,546-87,936,580

External References & Databases

Ensembl (ENSG00000174990)

Transcript & Mutation Effects

hg38 • Region Span ~55.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014332

Submitter: Labcorp Genetics (formerly Invitae)

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014332

Submitter: Orphanet

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014332

Submitter: Ambry Genetics

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014332

Submitter: G2P

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014332

Submitter: ClinGen

The CA5A gene has been associated with autosomal recessive hyperammonemia due to carbonic anhydrase VA deficiency using the ClinGen Clinical Validity Framework. CA5A was first associated with this disease in humans in 2014 (Karnebeek et al, PMID 24530203), and the association has been reported in 13 probands in 2 publications (Karnebeek et al, 2014, PMID 24530203; Diez-Fernandez et al, 2016, PMID 26913920). Six variants (including two missense, one nonsense, one splice site, one intronic deletion, and a single exon deletion) have been described in humans. Of note, deletion of exon 6 has been reported in six probands, all of whom are from the Indian subcontinent. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the biochemical function of the gene product (carbonic anhydrase VA), and a mouse model (Shah et al, 2013, PMID 23589845). In summary, CA5A is definitively associated with autosomal recessive hyperammonemia due to carbonic anhydrase VA deficiency. This classification was approved by the ClinGen Aminoacidopathies Expert Panel of the Inborn Errors of Metabolic Working Group on September 10th, 2018.

Clinical Genomic Database (CGD)

Carbonic anhydrase VA deficiencyAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: Medical treatment (eg, with N-carbamyl-L-glutamate (NCG) alone or with other treatments) has been reported as resolving hyperammonemia in affected individuals

Refs: 24530203; 26913920

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CA5A variants in ClinVar

5 Conditions Cataloged

Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiencyTotal: 167

Inborn genetic diseasesTotal: 63

not providedTotal: 39

CA5A-related disorderTotal: 19

not specifiedTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001739.2. 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	1 clinvar	55 clinvar	1 clinvar	58
missense	1 clinvar	2 clinvar	102 clinvar	15 clinvar	2 clinvar	122
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar				4
Total	5	8	104	70	3	190

Highest pathogenic variant AF is 0.00017164131

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001739.2	RefSeq	NP_001730.1	7	MANE Select
ENST00000649794.3	Ensembl	ENSP00000498065.2	7	MANE Select
NM_001367225.1	RefSeq	NP_001354154.1	7	Standard
ENST00000648022.1	Ensembl	ENSP00000497934.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ca5a	Danio rerio	Structure: whole organism Quality: necrotic abnormal

Gene / Model

Organism

Observed Phenotype

ca5a

Danio rerio

Structure: whole organism

Quality: necrotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nitrogen metabolism - Homo sapiens (human)
Metabolism
Reversible hydration of carbon dioxide

Biological Process

bicarbonate transport

Molecular Function

carbonate dehydratase activity
zinc ion binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000309893
Coding exons: 7
Length: 48511
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.20	222	177	1.25	0.0000108	1952
Missense (PolyPhen)		72	63.855	1.1275		741
Synonymous	-1.53	90	73.3	1.23	0.00000491	583
Loss of Function	1.65	9	16.2	0.556	7.75e-7	171

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	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Reversible hydration of carbon dioxide. Low activity.;
Disease: DISEASE: Hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD) [MIM:615751]: An autosomal recessive inborn error of metabolism, clinically characterized by infantile hyperammonemic encephalopathy. Metabolic abnormalities include hypoglycemia, hyperlactatemia, metabolic acidosis and respiratory alkalosis. {ECO:0000269|PubMed:24530203}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.482
RVIS EVS: 0
RVIS percentile EVS: 53.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.512

Gene Damage Prediction

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