EXOC8

protein-coding

exocyst complex component 8, the group of Exocyst complex|Pleckstrin homology domain containing

Gene summary

This gene encodes a component of the exocyst complex, an evolutionarily conserved multi-protein complex that plays a critical role in vesicular trafficking and the secretory pathway by targeting post-Golgi vesicles to the plasma membrane. This protein is a target of activated Ral subfamily of GTPases and thereby regulates exocytosis by tethering vesicles to the plasma membrane. Mutations in this gene may be related to Joubert syndrome. [provided by RefSeq, Sep 2016]

MANE transcript

NM_175876.5

Inheritance

ClinVar variants

P:2U:82B:21

Top phenotype

neurodevelopmental disorder with microcephaly, seizures, and brain atrophy

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr1:231,332,753-231,337,852

External References & Databases

Ensembl (ENSG00000116903)

Transcript & Mutation Effects

hg38 • Region Span ~5.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with microcephaly, seizures, and brain atrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033662

Submitter: Ambry Genetics

neurodevelopmental disorder with microcephaly, seizures, and brain atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033662

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 32103185 – Reports 1 family with a homozygous truncating (pLOF) EXOC8 variant (Asp607Ter) and phenotype including severe developmental delay, seizures, microcephaly, brain atrophy, and early death. Case-level (biallelic predicted null in AR model; homozygous scored once; no consanguinity deduction applied as not specified) = 1.5; segregation (familial support; conservative) = 0.5; case-control = 0. PMID: 35460391 – Reports a large consanguineous family with multiple affected individuals homozygous for a nonsense (pLOF) EXOC8 variant with consistent neurodevelopmental phenotype (microcephaly, seizures, developmental delay, brain atrophy). Case-level (biallelic predicted null; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (affected relatives; conservative) = 0.5; case-control = 0. Published genetic evidence total = case-level (1.5 + 1.0 = 2.5) + segregation (0.5 + 0.5 = 1.0) = 3.5/12. Genetic evidence – our case: 1 proband; homozygous predicted loss-of-function frameshift variant; autosomal recessive inheritance; consanguinity not specified; no additional genotyped affected relatives; no segregation or case-control data. Case-level (biallelic predicted null in AR model; homozygous scored once; no consanguinity deduction applied as not specified) = 1.5; segregation = 0; case-control = 0. Current case contribution = 1.5/12. Total genetic evidence (published + our case) = 5.0/12. Experimental evidence – Published: EXOC8 encodes a component of the exocyst complex involved in vesicle trafficking and neuronal development (biochemical function/biological plausibility) = 0.5. Model system and pathway-level evidence cited in GenCC (including PMID: 27626380, high-throughput mouse phenotyping showing developmental abnormalities in exocyst-related genes) provides supportive but not phenotype-specific functional evidence = 1.5. Experimental evidence total = 2.0/6. Overall score = 7.0

neurodevelopmental disorder with microcephaly, seizures, and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033662

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EXOC8 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 69

not providedTotal: 37

Neurodevelopmental disorder with microcephaly, seizures, and brain atrophyTotal: 5

Joubert syndromeTotal: 1

EXOC8-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_175876.5. 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				13 clinvar	4 clinvar	17
missense			80 clinvar	2 clinvar	2 clinvar	84
nonsense						0
start loss						0
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	0	2	82	15	6	105

Highest pathogenic variant AF is 0.0000043369596

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_175876.5	RefSeq	NP_787072.2	1	MANE Select
ENST00000366645.1	Ensembl	ENSP00000355605.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RalA downstream regulated genes
VxPx cargo-targeting to cilium
Cargo trafficking to the periciliary membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

exocyst assembly
endosome organization
protein transport
regulation of macroautophagy
extracellular matrix disassembly

Molecular Function

protein binding
Ral GTPase binding

Cellular Component

exocyst
late endosome
cytosol
plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360394
Coding exons: 1
Length: 5119
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.04	294	410	0.716	0.0000206	4730
Missense (PolyPhen)		54	116.93	0.4618		1309
Synonymous	-0.0547	171	170	1.01	0.00000881	1473
Loss of Function	4.40	1	24.5	0.0408	0.00000141	259

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

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: 0.116

Intolerance Scores

LoFtool: 0.117
RVIS EVS: -0.49
RVIS percentile EVS: 22.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.946

Gene Damage Prediction

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