EXOC6B
protein-codingexocyst complex component 6B, the group of Exocyst complex
Gene summary
This gene encodes a protein which is a part of the evolutionarily conserved exocyst, a multimeric protein complex necessary for exocytosis, which in turn, is crucial for cell growth, polarity and migration. Disruption of this gene may be associated with phenotypes exhibiting multiple symptoms including intellectual disability and developmental delay (DD). [provided by RefSeq, Jun 2016]
- SEC15L2
- SEC15B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~650.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0032724
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032724
Submitter: ClinGen
*EXOC6B* was first reported in association to autosomal recessive Spondyloepimetaphyseal Dysplasia with Joint Laxity, type 3 in 2016 (Girisha et al., PMID: 26669664). This entity is characterized by multiple joint dislocations, joint laxity, postnatal growth deficiency, scoliosis, leptodactyly, delayed carpal/tarsal bone ossification and spondylar, metaphyseal and epiphyseal dysplasia. It is currently the only phenotype asserted for this gene (OMIM #618395). To date, four different causal variants have been reported in the literature in six probands from four unrelated families - two private homozygous nonsense variants (PMIDs: 26669664 and 36150098), one homozygous multi-exon deletion (PMID: 30284759) and one homozygous single-exon deletion (PMID: 36150098). All reported cases were investigated using broad genetic testing strategies, which excluded other known causes for the skeletal dysplasia phenotype. Segregation analysis was consistent with the autosomal recessive mode of inheritance. A total of 10.5 points was reached for genetic evidence. The proposed mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by expression studies and functional alteration studies using both patients cells and non-patients cells submitted to knockdown of *EXOC6B* (PMIDs: 38305850, 38305850). Functional data show that the EXOC6B protein is expressed perinuclearly and at the base of the primary cilium in murine prechondrocytes cells, and its expression was significantly reduced following the targeted gene knockdown. Additionally, cells from affected patients exhibited reduced mRNA and/or protein expression of *EXOC6B*, along with defective ciliogenesis and impaired osteogenic differentiation capacity. The combined score for genetic and functional evidence reaches the threshold of 12 points, and this gene-disease relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. In summary, there is definitive evidence supporting the relationship between *EXOC6B* and autosomal recessive Spondyloepimetaphyseal Dysplasia with Joint Laxity, type 3. This classification was approved by the ClinGen Skeletal Disorders GCEP on July 2nd, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0019675
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0032724
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EXOC6B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015189.3. 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 | 5 | 62 | 7 | 74 | ||
| missense | 138 | 5 | 1 | 144 | ||
| nonsense | 4 | 4 | 5 | 13 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 2 | 1 | 4 | ||
| splice donor/acceptor (+/-2bp) | 5 | 5 | 10 | |||
| Total | 5 | 11 | 155 | 67 | 8 | 246 |
Highest pathogenic variant AF is 0.0000044015524
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_056004.1 | 22 | MANE Select | |
| Ensembl | ENSP00000272427.7 | 22 | MANE Select | |
| RefSeq | NP_001308658.1 | 23 | Standard | |
| RefSeq | NP_001308659.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- exocytosis
- Golgi to plasma membrane transport
- vesicle docking involved in exocytosis
- protein transport
Molecular Function
- protein binding
Cellular Component
- exocyst
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000272427
- Coding exons
- 22
- Length
- 650058
- Individuals with no LoFs
- 124616
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 124638
- p
- 0.0000883
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.09 | 299 | 419 | 0.713 | 0.0000218 | 5326 |
| Missense (PolyPhen) | 98 | 176.29 | 0.5559 | 2324 | ||
| Synonymous | 0.946 | 136 | 151 | 0.902 | 0.00000790 | 1449 |
| Loss of Function | 4.90 | 12 | 49.1 | 0.245 | 0.00000278 | 575 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00063 | 0.00058 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000036 | 0.000035 | rare |
| South Asian | 0.00014 | 0.00013 | rare |
| Other | 0.00017 | 0.00017 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.;
Recessive Scores
- pRec
- 0.111
Intolerance Scores
- RVIS EVS
- -0.87
- RVIS percentile EVS
- 10.8
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.208
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |