CNTN6

protein-coding

contactin 6, the group of Contactins|I-set domain containing

Gene summary

The protein encoded by this gene is a member of the immunoglobulin superfamily. It is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

MANE transcript

NM_001289080.2

Inheritance

ClinVar variants

P:3U:197B:51

Top phenotype

CNTN6-related disorder

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr3:1,092,658-1,404,217

External References & Databases

Ensembl (ENSG00000134115)

Transcript & Mutation Effects

hg38 • Region Span ~311.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Variants involving *CNTN6* have been reported in individuals with varying neurodevelopmental presentations (intellectual disability, autism spectrum disorder, ADHD, developmental delay), neuropsychiatric disorders (schizophrenia, bipolar disorder, depression), hypotonia, seizures, cardiac anomalies, low weight, microcephaly and dysmorphic features as early as 2014 (PMIDs: 25606055, 26257835, 27166760, 30508811). To date, all reported variants have been copy number changes; no individuals with presumed protein-altering single nucleotide variants in *CNTN6* and demonstrable phenotypes have been reported. The observed copy number changes include both multigenic events (deletions and duplications involving *CNTN6* in addition to other genes), as well as deletions involving *CNTN6* alone. The multigenic events are not counted as evidence in this evaluation as the role of the other genes in the presenting phenotype cannot be excluded. Single gene and intragenic deletions reported to date have been inherited from both affected and reportedly unaffected parents. In some cases, additional copy number variants were also observed. Additionally, *CNTN6* is not constrained for loss-of-function variants (pLI = 0, gnomAD v2.1.1) and *CNTN6* variants are seen at high enough frequencies in the non-affected population that it is difficult to assess the potential pathogenicity of these variants. For these reasons, all cases have been scored at 0. Although some authors have suggested that variants in *CNTN6* could be involved in neurodevelopmental disorders with reduced penetrance, more information is needed to determine the role of *CNTN6* in disease. In summary, there is limited evidence to support the relationship between *CNTN6* and complex neurodevelopmental disorder and the final classification is disputed. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 20, 2022 (SOP9).

Tourette syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNTN6 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 210

CNTN6-related disorderTotal: 37

not providedTotal: 27

Autism spectrum disorderTotal: 1

Autistic behaviorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001289080.2. 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			3 clinvar	22 clinvar	5 clinvar	30
missense			185 clinvar	18 clinvar	5 clinvar	208
nonsense		1 clinvar	2 clinvar		1 clinvar	4
start loss						0
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)		1 clinvar	5 clinvar			6
Total	0	3	197	40	11	251

Highest pathogenic variant AF is 0.0000012428706

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001289080.2	RefSeq	NP_001276009.1	22	MANE Select
ENST00000446702.7	Ensembl	ENSP00000407822.2	22	MANE Select
NM_001289081.2	RefSeq	NP_001276010.1	20	Standard
NM_001349350.2	RefSeq	NP_001336279.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pathways Affected in Adenoid Cystic Carcinoma
Canonical and Non-canonical Notch signaling
Developmental Biology
CHL1 interactions
L1CAM interactions

Biological Process

cell adhesion
homophilic cell adhesion via plasma membrane adhesion molecules
Notch signaling pathway
axon guidance
central nervous system development

Molecular Function

Notch binding
cell-cell adhesion mediator activity

Cellular Component

plasma membrane
axon
parallel fiber to Purkinje cell synapse
anchored component of presynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000446702
Coding exons: 22
Length: 311642
Individuals with no LoFs: 125279
Homozygous LoFs: 1
Heterozygous LoFs: 467
Defined: 125747
p: 0.00186

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-3.00	735	539	1.36	0.0000265	6690
Missense (PolyPhen)		285	227.64	1.252		2851
Synonymous	-3.62	258	194	1.33	0.00000996	1973
Loss of Function	0.620	49	53.9	0.909	0.00000271	655

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.0030	0.0028	notable
Ashkenazi Jewish	0.013	0.013	notable
East Asian	0.0019	0.0019	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0013	0.0012	notable
South Asian	0.0015	0.0014	notable
Other	0.00099	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Contactins mediate cell surface interactions during nervous system development. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Involved in motor coordination (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.131

Intolerance Scores

LoFtool: 0.974
RVIS EVS: -0.92
RVIS percentile EVS: 9.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.140

Gene Damage Prediction

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