CLDN14

protein-coding

claudin 14, 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. The encoded protein also binds specifically to the WW domain of Yes-associated protein. Defects in this gene are the cause of an autosomal recessive form of nonsyndromic sensorineural deafness. It is also reported that four synonymous variants in this gene are associated with kidney stones and reduced bone mineral density. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2010]

Previous symbols:

DFNB29

MANE transcript

NM_001146079.2

Inheritance

ClinVar variants

P:23U:98B:42

Top phenotype

Deafness, autosomal recessive 29

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr21:36,460,621-36,576,569

External References & Databases

Ensembl (ENSG00000159261)

Transcript & Mutation Effects

hg38 • Region Span ~115.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between CLDN14 and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/17/2017. Variants in CLDN14 were first reported in humans with this disease as early as 2001 (Wilcox et al.). At least 7 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 12 probands in 6 publications (11163249, 20811388, 22246673, 23235333, 27870113, 27838790). Variants in this gene segregated with disease in at least 49 additional family members. Many of the reported variants are believed to be founder variants from Pakistan and Newfoundland and Labrador Province. This gene-disease association is supported by a knockout mouse model and additional expression and functional alteration evidence. In summary, CLDN14 is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 29DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013537

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 29STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013537

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 29AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 11163249; 22246673

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLDN14 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 108

Autosomal recessive nonsyndromic hearing loss 29Total: 43

Inborn genetic diseasesTotal: 38

CLDN14-related disorderTotal: 22

not specifiedTotal: 20

Vein of Galen aneurysmal malformationTotal: 6

Hearing impairmentTotal: 5

Hearing loss, autosomal recessiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001146079.2. 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			4 clinvar	36 clinvar	3 clinvar	43
missense	2 clinvar	5 clinvar	89 clinvar	3 clinvar		99
nonsense	4 clinvar	3 clinvar				7
start loss			1 clinvar			1
frameshift	7 clinvar	2 clinvar	4 clinvar			13
splice donor/acceptor (+/-2bp)						0
Total	13	10	98	39	3	163

Highest pathogenic variant AF is 0.0007118412

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_001146079.2	RefSeq	NP_001139551.1	1	MANE Select
ENST00000399135.6	Ensembl	ENSP00000382087.1	1	MANE Select
NM_001146077.2	RefSeq	NP_001139549.1	1	Standard
NM_001146078.3	RefSeq	NP_001139550.1	1	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

calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules
protein-containing complex assembly

Molecular Function

structural molecule activity
identical protein binding

Cellular Component

endoplasmic reticulum
plasma membrane
bicellular tight junction
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399137
Coding exons: 1
Length: 115949
Individuals with no LoFs: 125691
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125713
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.197	148	155	0.956	0.0000107	1512
Missense (PolyPhen)		55	64.454	0.85332		643
Synonymous	-0.354	81	77.0	1.05	0.00000637	538
Loss of Function	0.0745	6	6.20	0.968	2.74e-7	59

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium- independent cell-adhesion activity. {ECO:0000250}.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.0819
RVIS EVS: -0.6
RVIS percentile EVS: 17.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.618

Gene Damage Prediction

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