CLDN16
protein-codingclaudin 16, the group of Claudins
Gene summary
Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~89.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009550
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009550
Submitter: ClinGen
The *CLDN16* gene is located on chromosome 3 at 3q28. *CLDN16* encodes the renal tight junction protein claudin-16 which participates in the paracellular reabsorption of calcium and magnesium in the thick ascending limb of the loop of Henle (PMID: 18003771). *CLDN16* was first reported in relation to autosomal recessive renal hypomagnesemia, type 3 (OMIM: 248250) in 1999 (Simon et al., PMID: 10390358). The preferred disease name suggested for this disorder is 'autosomal recessive renal hypomagnesemia with hypercalciuria and nephrocalcinosis - *CLDN16*'. This progressive renal tubular disorder is characterized by excessive urinary losses of calcium and magnesium (PMID: 26613020). The mechanism of pathogenicity is known to be loss of function. 13 variants (9 missense, 1 start-loss, 1 splice, 1 deletion and 1 nonsense) have been reported in nine probands in four publications (PMID: 10390358, 11518780, 18003771, 32869508) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression, biochemical function, protein-protein interactions, and an animal model (PMID: 17442678, 10390358, 18188451). A total of 3.5/6 pts. for experimental evidence was reached In summary, there is definitive evidence supporting the relationship between *CLDN16* and autosomal recessive renal hypomagnesemia, type 3 (OMIM: 248250). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0009550
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Renal
Intervention: Renal
Rationale: Presentation can include hypocalcemic/hypomagnesemic seizures, and early diagnosis and magnesium therapy can be beneficial; Renal transplantation is frequently necessary
Comments: Some individuals have a self-limiting form of disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CLDN16 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006580.4. 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 | 2 | 30 | 32 | |||
| missense | 14 | 18 | 64 | 2 | 2 | 100 |
| nonsense | 5 | 3 | 1 | 9 | ||
| start loss | 1 | 2 | 1 | 4 | ||
| frameshift | 3 | 3 | 1 | 7 | ||
| splice donor/acceptor (+/-2bp) | 3 | 4 | 7 | |||
| Total | 23 | 29 | 73 | 32 | 2 | 159 |
Highest pathogenic variant AF is 0.00006381692
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006571.2 | 5 | MANE Select | |
| Ensembl | ENSP00000264734.3 | 5 | MANE Select | |
| RefSeq | NP_001365421.1 | 5 | Standard | |
| RefSeq | NP_001365422.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Tight junction - Homo sapiens (human)
- Hepatitis C - Homo sapiens (human)
- Leukocyte transendothelial migration - Homo sapiens (human)
- EMT transition in Colorectal Cancer
Biological Process
- cellular metal ion homeostasis
- excretion
- calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules
- magnesium ion transmembrane transport
Molecular Function
- structural molecule activity
- protein binding
- magnesium ion transmembrane transporter activity
- identical protein binding
Cellular Component
- plasma membrane
- bicellular tight junction
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264734
- Coding exons
- 5
- Length
- 89603
- Individuals with no LoFs
- 125738
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125748
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0768 | 173 | 170 | 1.02 | 0.00000962 | 1957 |
| Missense (PolyPhen) | 54 | 58.51 | 0.92293 | 693 | ||
| Synonymous | -1.25 | 79 | 66.1 | 1.20 | 0.00000410 | 626 |
| Loss of Function | 2.21 | 5 | 13.9 | 0.360 | 7.51e-7 | 160 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium- independent cell-adhesion activity. Involved in paracellular magnesium reabsorption. Required for a selective paracellular conductance. May form, alone or in partnership with other constituents, an intercellular pore permitting paracellular passage of magnesium and calcium ions down their electrochemical gradients. Alternatively, it could be a sensor of magnesium concentration that could alter paracellular permeability mediated by other factors.;
Recessive Scores
- pRec
- 0.194
Intolerance Scores
- LoFtool
- 0.145
- RVIS EVS
- -0.14
- RVIS percentile EVS
- 43.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.265
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |