CNTNAP1

protein-coding

contactin associated protein 1, the group of Contactin associated protein family

Gene summary

The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for 'contactin-associated protein,' includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. [provided by RefSeq, Jan 2009]

Previous symbols:

NRXN4

MANE transcript

NM_003632.3

Inheritance

ClinVar variants

P:53U:294B:150

Top phenotype

Lethal congenital contracture syndrome 7; Neuropathy, congenital hypomyelinating, 3

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr17:42,682,531-42,699,993

External References & Databases

Ensembl (ENSG00000108797)

Transcript & Mutation Effects

hg38 • Region Span ~17.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypomyelination neuropathy-arthrogryposis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017049

Submitter: Orphanet

lethal congenital contracture syndrome 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014569

Submitter: G2P

lethal congenital contracture syndrome 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014569

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Lethal congenital contracture syndrome 7; Neuropathy, congenital hypomyelinating, 3AR

Manifestation: Musculoskeletal; 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: 24319099; 27782105; 27668699; 28374019; 29511323

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNTNAP1 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 446

Inborn genetic diseasesTotal: 161

not specifiedTotal: 48

Neuropathy, congenital hypomyelinating, 3Total: 34

CNTNAP1-related disorderTotal: 34

Lethal congenital contracture syndrome 7Total: 25

Congenital hypomyelination neuropathy with or without arthrogryposisTotal: 2

Fetal akinesia deformation sequence 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003632.3. 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			4 clinvar	132 clinvar	6 clinvar	142
missense	1 clinvar	8 clinvar	284 clinvar	11 clinvar	1 clinvar	305
nonsense	13 clinvar	7 clinvar	3 clinvar			23
start loss		1 clinvar				1
frameshift	8 clinvar	5 clinvar	1 clinvar			14
splice donor/acceptor (+/-2bp)	5 clinvar	5 clinvar	2 clinvar			12
Total	27	26	294	143	7	497

Highest pathogenic variant AF is 0.000021683642

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003632.3	RefSeq	NP_003623.1	24	MANE Select
ENST00000264638.9	Ensembl	ENSP00000264638.3	24	MANE Select
ENST00000591662.1	Ensembl	ENSP00000466571.1	15	Standard
ENST00001107340.1	Ensembl	ENSP00000777145.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Developmental Biology
Neurofascin interactions
L1CAM interactions
Axon guidance

Biological Process

protein localization to paranode region of axon
cytoskeleton organization
cell adhesion
signal transduction
positive regulation of signal transduction

Molecular Function

SH3/SH2 adaptor activity
protein binding
SH3 domain binding
signaling receptor activity

Cellular Component

integral component of plasma membrane
voltage-gated potassium channel complex
integral component of membrane
paranodal junction
paranode region of axon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264638
Coding exons: 24
Length: 17202
Individuals with no LoFs: 125674
Homozygous LoFs: 0
Heterozygous LoFs: 74
Defined: 125748
p: 0.000294

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.22	630	902	0.698	0.0000606	8937
Missense (PolyPhen)		180	302.03	0.59596		3099
Synonymous	1.38	334	368	0.909	0.0000245	2873
Loss of Function	5.79	24	79.9	0.300	0.00000527	726

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00020	0.00017	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00026	0.00026	rare
South Asian	0.00023	0.00023	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required, with CNTNAP2, for radial and longitudinal organization of myelinated axons. Plays a role in the formation of functional distinct domains critical for saltatory conduction of nerve impulses in myelinated nerve fibers. Demarcates the paranodal region of the axo-glial junction. In association with contactin involved in the signaling between axons and myelinating glial cells. {ECO:0000269|PubMed:24319099, ECO:0000269|PubMed:27818385, ECO:0000269|PubMed:28374019}.;
Disease: DISEASE: Note=Defects in CNTNAP1 are associated with congenital hypomyelinating neuropathy (CHN). Patients show polyhydramnios and reduced fetal movements, they were hypotonic and required ventilatory support at birth. But no arthrogryposis is noted. Patients die often early in the neonatal period. {ECO:0000269|PubMed:27668699, ECO:0000269|PubMed:27818385, ECO:0000269|PubMed:28374019}.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.278
RVIS EVS: -2.3
RVIS percentile EVS: 1.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.811

Gene Damage Prediction

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