CNTNAP5

protein-coding

contactin associated protein family member 5, the group of Contactin associated protein family

Gene summary

This gene product belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, and thrombospondin N-terminal-like domains. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001367498.1

Inheritance

ClinVar variants

U:198B:29

Top phenotype

CNTNAP5-related disorder

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr2:124,025,287-124,921,219

External References & Databases

Ensembl (ENSG00000155052)

Transcript & Mutation Effects

hg38 • Region Span ~895.9 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

*CNTNAP5* was first reported in relation to autism spectrum disorder in 2010 (PMID: 20346443) when a deletion disrupting this gene was identified in a pair of siblings with autism who were also found to have additional microdeletions. Since that time, several other variants in *CNTNAP5* have been reported in individuals with various neurodevelopmental presentations including autism, intellectual disability, seizures, and language impairment. Because of this the Intellectual Disability and Autism Gene Curation Expert Panel decided to curate this evidence using the term complex neurodevelopmental disorder. At least 10 individuals with variants (mainly missense with a few intragenic and intergenic deletion variants) in this gene have been reported (PMIDs: 20346443, 31398340, 35982159, 37007974, 37543562). However, none of them were assigned scores. In some cases, the variants reported were either inherited from unaffected parents or found at high frequencies in gnomAD v4.1. In other cases, the probands had other variants in other genes that could also be suspected to be causative for complex neurodevelopmental disorders. Additionally, there are a few reports of individuals with intragenic copy number variants in this gene; these were also excluded from case level evidence given the presence of the same variants in unaffected family members, or the presence of additional copy number variants in the same proband (PMIDs: 23275889, 32329157, 34553698). These findings are consistent with the fact that *CNTNAP5* is not constrained for either loss-of-function variants (pLI = 0, LOEUF = 0.58, gnomAD v4.1.1) or missense variants (Z = -0.1). In summary, the evidence supporting the relationship between *CNTNAP5* and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *CNTNAP5* plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 20, 2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNTNAP5 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 176

CNTNAP5-related disorderTotal: 34

not providedTotal: 31

CNTNAP5-associated intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367498.1. 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			2 clinvar	16 clinvar	4 clinvar	22
missense			188 clinvar	6 clinvar	3 clinvar	197
nonsense			2 clinvar			2
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	198	22	7	227

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001367498.1	RefSeq	NP_001354427.1	24	MANE Select
ENST00000682447.1	Ensembl	ENSP00000508115.1	24	MANE Select
NM_130773.4	RefSeq	NP_570129.1	24	Standard
ENST00000431078.1	Ensembl	ENSP00000399013.1	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cell adhesion

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000431078
Coding exons: 24
Length: 890001
Individuals with no LoFs: 124751
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 124777
p: 0.000104

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.388	700	729	0.960	0.0000407	8551
Missense (PolyPhen)		176	247.43	0.71131		3019
Synonymous	-1.16	324	299	1.09	0.0000185	2497
Loss of Function	6.24	12	67.2	0.178	0.00000375	745

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000099	0.000097	rare
South Asian	0.000066	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in the correct development and proper functioning of the peripheral and central nervous system and be involved in cell adhesion and intercellular communication.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.298
RVIS EVS: -0.99
RVIS percentile EVS: 8.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.446

Gene Damage Prediction

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