GJB6
protein-codinggap junction protein beta 6, the group of Gap junction proteins
Gene summary
Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]
- DFNA3
- ED2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012977
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019497
Submitter: ClinGen
The GJB6 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/21/2017. The GJB6-D13S1830 deletion is a relatively common disease allele in many populations and is classified as pathogenic for hearing loss, frequently identified in homozygosity or in trans with a pathogenic GJB2 variant. This is a deletion of approximately 309kb of DNA including the 5' end of GJB6 and a region upstream of both GJB6 and the GJB2 gene. It has been proposed that GJB6 and GJB2 are co-regulated by a cis-acting element (Ahmad 2007 PMID 17227867). Their protein products, connexin 30 and 26 (Cx30 and Cx26), respectively, co-localize in the supporting cells of mouse cochlea (Ahmad 2003 PMID 12859965; Forge 2003 PMID 14595769) but not human cochlea (Liu 2016 PMID 26941236). Deletion of the GJB6 gene, including surrounding regulatory regions, in mice causes hearing loss (Teubner 2003 PMID 12490528). Exogenous Cx30 and Cx26 could both rescue the hearing loss in this mouse (Ahmad 2007 PMID 17227867; Qu 2012 PMID 22142852). However, an independent mouse model with only the coding sequence of GJB6 deleted and no surrounding sequence deleted had normal hearing, suggesting that the regulatory region 5' of GJB6 but not the gene itself is necessary for normal hearing in mice. Furthermore, many deletions upstream of both GJB6 and GJB2 are pathogenic for hearing loss without disruption of GJB6 (Wilch 2010 PMID 20236118; Abou Tayoun 2016 PMID 26444186). This gene has also been implicated in Clouston syndrome. This association has been assessed separately. In summary, there is convincing evidence refuting the association between GJB6 and autosomal recessive nonsyndromic hearing loss, which significantly outweighs the evidence supporting the association. This classification was approved by the ClinGen Hearing Loss Working Group on 4/17/2018.
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: ClinGen
The GJB6 gene has been associated with autosomal dominant Clouston syndrome using the ClinGen Clinical Validity Framework as of 4/13/18. This association was made using case-level data. At least 8 missense variants have been reported in humans. GJB6 was first associated with this disease in humans as early as 2000 (Lemartine et al.). Association is seen in at least 13 probands in 8 publications (11017065, 23219093, 11874494, 18717672, 27137747, 25808784, 19416251, 26620415). Variants in this gene segregated with disease in 65 additional family members. The GJB6 and autosomal dominant Clouston syndrome association is supported by expression studies. Of note, this gene has also been implicated in nonsyndromic hearing loss. Autosomal recessive nonsyndromic hearing loss has been assessed separately. There was not enough evidence to split out and curate for autosomal dominant nonsyndromic hearing loss, however it should be noted this curation did not score any AD nonsyndromic hearing loss cases. Expert review upgraded the GJB6-Clouston syndrome association to Definitive. In summary, GJB6 is definitively associated with autosomal dominant Clouston syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 4/17/18.
Inheritance Pattern: AD
Disease ID:MONDO:0012975
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012977
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012977
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012975
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019588
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012977
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012975
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018781
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007510
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dental; Dermatologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: Digenic inheritance (eg, with GJB2) has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GJB6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001110219.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 33 | 1 | 38 | ||
| missense | 4 | 4 | 86 | 7 | 101 | |
| nonsense | 2 | 2 | 4 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 2 | 10 | 13 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 5 | 9 | 104 | 40 | 1 | 159 |
Highest pathogenic variant AF is 0.000018601813
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001103689.1 | 1 | MANE Select | |
| Ensembl | ENSP00000493834.1 | 1 | MANE Select | |
| RefSeq | NP_001103690.1 | 1 | Standard | |
| RefSeq | NP_001103691.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cx30.3 | Danio rerio | Structure: sagitta Quality: decreased width abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Hair Follicle Development- Induction (Part 1 of 3)
- Calcium Regulation in the Cardiac Cell
Biological Process
- apoptotic process
- cell communication
- aging
- sensory perception of sound
- negative regulation of cell population proliferation
Cellular Component
- cytosol
- connexin complex
- integral component of membrane
- apical plasma membrane
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356192
- Coding exons
- 1
- Length
- 10425
- Individuals with no LoFs
- 125554
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 194
- Defined
- 125748
- p
- 0.000772
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.453 | 134 | 150 | 0.896 | 0.00000863 | 1737 |
| Missense (PolyPhen) | 47 | 62.111 | 0.75671 | 749 | ||
| Synonymous | -0.493 | 69 | 64.0 | 1.08 | 0.00000429 | 502 |
| Loss of Function | -0.211 | 10 | 9.31 | 1.07 | 6.67e-7 | 84 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.0016 | 0.0016 | notable |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.0011 | 0.0011 | notable |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.0018 | 0.0018 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.;
- Disease
- DISEASE: Ectodermal dysplasia 2, Clouston type (ECTD2) [MIM:129500]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD2 is an autosomal dominant condition characterized by atrichosis, nail hypoplasia and deformities, hyperpigmentation of the skin, normal teeth, normal sweat and sebaceous gland function. Palmoplantar hyperkeratosis is a frequent feature. Hearing impairment has been detected in few cases. {ECO:0000269|PubMed:11017065, ECO:0000269|PubMed:11874494}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 1B (DFNB1B) [MIM:612645]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:11807148, ECO:0000269|PubMed:15994881}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 3B (DFNA3B) [MIM:612643]: A form of non-syndromic sensorineural hearing loss characterized by a variable phenotype, ranging from bilateral middle to high frequency hearing loss to profound sensorineural deafness. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:10471490}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.322
Intolerance Scores
- LoFtool
- 0.0864
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 70.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.450
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |