CNTN2

protein-coding

contactin 2, the group of Contactins|I-set domain containing

Gene summary

This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

Previous symbols:

MANE transcript

NM_005076.5

Inheritance

AR, AD

ClinVar variants

P:43U:345B:293

Top phenotype

Epilepsy, early-onset, 5, with or without developmental delay

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr1:205,042,937-205,078,289

External References & Databases

Ensembl (ENSG00000184144)

Transcript & Mutation Effects

hg38 • Region Span ~35.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsy, familial adult myoclonic, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014167

Submitter: Labcorp Genetics (formerly Invitae)

epilepsy, familial adult myoclonic, 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014167

Submitter: Ambry Genetics

benign adult familial myoclonic epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019448

Submitter: Orphanet

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

Biallelic *CNTN2* variants were first reported in individuals with epilepsy, tremors, and myoclonus in 2013 (Stogmann et al., PMID: 23518707). Since then, additional patients with homozygous *CNTN2* variants have been reported with developmental delays/intellectual disability, most of whom also have epilepsy (PMIDs: 37359369, 34691156). Five variants (nonsense, frameshift) that have been reported in five probands in five publications are included in this curation (PMIDs: 23518707, 34691156, 36553572, 37359369, 28397838). Multiple affected individuals have been observed within families (PMIDs: 23518707, 37359369). This gene-disease relationship is also supported by a mouse model in which homozygous null *CNTN2* mice present with spontaneous seizures (PMID: 11178983). In summary, there is definitive evidence supporting the relationship between *CNTN2* and autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date November 7, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Epilepsy, early-onset, 5, with or without developmental delayAR

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: 23518707

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNTN2 variants in ClinVar

7 Conditions Cataloged

Epilepsy, familial adult myoclonic, 5Total: 817

not specifiedTotal: 128

not providedTotal: 45

CNTN2-related disorderTotal: 14

Cerebellar atrophy, visual impairment, and psychomotor retardation;Total: 1

Epilepsy, familial adult myoclonic, 1Total: 1

Complex neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005076.5. 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			6 clinvar	251 clinvar	8 clinvar	265
missense			337 clinvar	30 clinvar	4 clinvar	371
nonsense	14 clinvar	5 clinvar				19
start loss						0
frameshift	11 clinvar	2 clinvar				13
splice donor/acceptor (+/-2bp)		11 clinvar	2 clinvar			13
Total	25	18	345	281	12	681

Highest pathogenic variant AF is 0.00011030551

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005076.5	RefSeq	NP_005067.1	22	MANE Select
ENST00000331830.7	Ensembl	ENSP00000330633.4	22	MANE Select
NM_001346083.2	RefSeq	NP_001333012.1	22	Standard
ENST00000532366.2	Ensembl	ENSP00000491665.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cntn2	Danio rerio	Structure: medial longitudinal fasciculus Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

cntn2

Danio rerio

Structure: medial longitudinal fasciculus

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Developmental Biology
NrCAM interactions
NCAM signaling for neurite out-growth
L1CAM interactions

Biological Process

microtubule cytoskeleton organization
cell adhesion
homophilic cell adhesion via plasma membrane adhesion molecules
axon guidance
axonal fasciculation

Molecular Function

carbohydrate binding
identical protein binding
protein self-association
cell-cell adhesion mediator activity

Cellular Component

plasma membrane
voltage-gated potassium channel complex
cell surface
axon
node of Ranvier

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331830
Coding exons: 22
Length: 35303
Individuals with no LoFs: 125599
Homozygous LoFs: 1
Heterozygous LoFs: 148
Defined: 125748
p: 0.000593

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.59	481	669	0.719	0.0000432	6702
Missense (PolyPhen)		165	269.87	0.61141		2649
Synonymous	1.02	254	276	0.922	0.0000186	2178
Loss of Function	4.92	16	55.6	0.288	0.00000324	550

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00069	0.00068	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0.0018	0.0018	notable
East Asian	0.00099	0.00098	rare
Finnish	0.00084	0.00083	rare
European (Non-Finnish)	0.00056	0.00055	rare
South Asian	0.00013	0.00013	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: In conjunction with another transmembrane protein, CNTNAP2, contributes to the organization of axonal domains at nodes of Ranvier by maintaining voltage-gated potassium channels at the juxtaparanodal region. May be involved in cell adhesion. {ECO:0000269|PubMed:23518707}.;
Disease: DISEASE: Epilepsy, familial adult myoclonic, 5 (FAME5) [MIM:615400]: A form of cortical myoclonic tremor with epilepsy, a syndrome characterized by cortical myoclonus and variable occurrence of epileptic seizures. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom; both complex partial as well as generalized tonic clonic seizures are described. Some patients exhibit mild cognitive impairment. {ECO:0000269|PubMed:23518707}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.188

Intolerance Scores

LoFtool: 0.595
RVIS EVS: -0.19
RVIS percentile EVS: 39.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.402

Gene Damage Prediction

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