CPLX1

protein-coding

complexin 1

Gene summary

Proteins encoded by the complexin/synaphin gene family are cytosolic proteins that function in synaptic vesicle exocytosis. These proteins bind syntaxin, part of the SNAP receptor. The protein product of this gene binds to the SNAP receptor complex and disrupts it, allowing transmitter release. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006651.4

Inheritance

ClinVar variants

P:4U:39B:21

Top phenotype

Developmental and epileptic encephalopathy 63

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr4:784,957-826,129

External References & Databases

Ensembl (ENSG00000168993)

Transcript & Mutation Effects

hg38 • Region Span ~41.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 63STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033372

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 63AR

Manifestation: 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: 26539891; 28422131

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CPLX1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 54

Inborn genetic diseasesTotal: 25

CPLX1-related disorderTotal: 10

Developmental and epileptic encephalopathy, 63Total: 6

not specifiedTotal: 5

4p partial monosomy syndromeTotal: 1

Abnormal brain morphologyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006651.4. 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				20 clinvar		20
missense		1 clinvar	38 clinvar	1 clinvar		40
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)						0
Total	0	4	39	21	0	64

Highest pathogenic variant AF is 0.00007251441

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006651.4	RefSeq	NP_006642.1	3	MANE Select
ENST00000304062.11	Ensembl	ENSP00000305613.6	3	MANE Select
ENST00000504062.1	Ensembl	ENSP00000421947.1	2	Standard
ENST00000505203.1	Ensembl	ENSP00000425960.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Synaptic Vesicle Pathway
Neuronal System
Glutamate Neurotransmitter Release Cycle
Dopamine Neurotransmitter Release Cycle

Biological Process

exocytosis
chemical synaptic transmission
synaptic vesicle exocytosis
regulation of exocytosis
insulin secretion

Molecular Function

SNARE binding
neurotransmitter transporter activity
protein binding
syntaxin-1 binding

Cellular Component

cytosol
dendrite
SNARE complex
neuronal cell body
terminal bouton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304062
Coding exons: 3
Length: 41242
Individuals with no LoFs: 122001
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 122004
p: 0.0000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.351	93	83.9	1.11	0.00000463	871
Missense (PolyPhen)		48	38.58	1.2442		401
Synonymous	-1.98	51	35.9	1.42	0.00000219	238
Loss of Function	2.22	0	5.75	0.00	2.44e-7	75

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)	0.000027	0.000027	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles (PubMed:21785414). Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse (PubMed:21785414). Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior. {ECO:0000250|UniProtKB:P63040, ECO:0000269|PubMed:21785414}.;

Intolerance Scores

RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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