EXOC2

protein-coding

exocyst complex component 2, the group of IPT domain containing|Exocyst complex

Gene summary

The protein encoded by this gene is a component of the exocyst complex, a multi-protein complex essential for the polarized targeting of exocytic vesicles to specific docking sites on the plasma membrane. Though best characterized in yeast, the component proteins and the functions of the exocyst complex have been demonstrated to be highly conserved in higher eukaryotes. At least eight components of the exocyst complex, including this protein, are found to interact with the actin cytoskeletal remodeling and vesicle transport machinery. This interaction has been shown to mediate filopodia formation in fibroblasts. This protein has been shown to interact with the Ral subfamily of GTPases and thereby mediate exocytosis by tethering vesicles to the plasma membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

Previous symbols:

SEC5L1

MANE transcript

NM_018303.6

Inheritance

ClinVar variants

P:1U:130B:16

Top phenotype

Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr6:485,154-693,139

External References & Databases

Ensembl (ENSG00000112685)

Transcript & Mutation Effects

hg38 • Region Span ~208.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859141

Submitter: PanelApp Australia

neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0859141

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*EXOC2* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2020 (Van Bergen et al., PMID: 32639540). Phenotypic features reported in affected individuals include developmental delay, intellectual disability, dysmorphisms, brain abnormalities, and poor motor skills. Three variants (1 nonsense and 2 missense) have been reported in the literature. One variant in *EXOC2*, reported in 2 homozygous individuals in one consanguineous family, is included in this curation (PMID: 32639540). This gene-disease relationship is also supported by rescue in patient cells and a *Drosophila* model. Defects in protein expression, global vesicle fusion rates, and cargo delivery in patient fibroblasts were restored to wild-type levels upon transduction of wild-type *EXOC2* (PMID: 32639540). Additionally, knockout of *EXOC2* expression in *Drosophila melanogaster* resulted in impairment of neuromuscular junction growth, neurite outgrowth, and vesicle trafficking to the plasma membrane (PMID: 12575951). Of note, an additional proband with compound heterozygous missense variants has been reported (PMID: 32639540). However, there is conflicting experimental functional evidence using patient cells. Out of caution, evidence for this proband and the missense variants has not been scored as additional evidence is needed to further demonstrate a relationship between these missense variants and disease. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 1, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasiaAR

Manifestation: Craniofacial; Neurologic

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

Refs: 32639540

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EXOC2 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 183

not providedTotal: 23

Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasiaTotal: 9

EXOC2-related disorderTotal: 3

Amelogenesis imperfecta type 1FTotal: 2

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018303.6. 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 clinvar	12 clinvar	3 clinvar	20
missense	1 clinvar		116 clinvar		1 clinvar	118
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	1	0	130	12	4	147

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018303.6	RefSeq	NP_060773.3	27	MANE Select
ENST00000230449.9	Ensembl	ENSP00000230449.4	27	MANE Select
ENST00000443083.5	Ensembl	ENSP00000406400.1	3	Standard
ENST00000870874.1	Ensembl	ENSP00000540933.1	27	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
exoc2	Danio rerio	Structure: orbital region Quality: increased accumulation abnormal

Gene / Model

Organism

Observed Phenotype

exoc2

Danio rerio

Structure: orbital region

Quality: increased accumulation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ras signaling pathway - Homo sapiens (human)
RalA downstream regulated genes
Chromosomal and microsatellite instability in colorectal cancer
Ras Signaling
Arf6 trafficking events

Biological Process

exocytosis
Golgi to plasma membrane transport
protein transport
vesicle-mediated transport
regulation of entry of bacterium into host cell

Molecular Function

protein binding
Ral GTPase binding
protein kinase binding
protein N-terminus binding

Cellular Component

exocyst
cytosol
plasma membrane
membrane
Flemming body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000230449
Coding exons: 27
Length: 207985
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.70	393	500	0.786	0.0000269	6071
Missense (PolyPhen)		133	199.52	0.66659		2374
Synonymous	-0.228	194	190	1.02	0.0000112	1709
Loss of Function	4.12	25	59.2	0.422	0.00000306	695

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00027	0.00027	rare
South Asian	0.00016	0.00016	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.;

Recessive Scores

pRec: 0.153

Intolerance Scores

LoFtool: 0.754
RVIS EVS: -0.97
RVIS percentile EVS: 8.9

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.959

Gene Damage Prediction

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