NRCAM

protein-coding

neuronal cell adhesion molecule, the group of Ig-like cell adhesion molecule family|Fibronectin type III domain containing|I-set domain containing

Gene summary

Cell adhesion molecules (CAMs) are members of the immunoglobulin superfamily. This gene encodes a neuronal cell adhesion molecule with multiple immunoglobulin-like C2-type domains and fibronectin type-III domains. This ankyrin-binding protein is involved in neuron-neuron adhesion and promotes directional signaling during axonal cone growth. This gene is also expressed in non-neural tissues and may play a general role in cell-cell communication via signaling from its intracellular domain to the actin cytoskeleton during directional cell migration. Allelic variants of this gene have been associated with autism and addiction vulnerability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001037132.4

Inheritance

ClinVar variants

P:16U:201B:24

Top phenotype

Neurodevelopmental disorder with neuromuscular and skeletal abnormalities

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr7:108,147,623-108,456,717

External References & Databases

Ensembl (ENSG00000091129)

Transcript & Mutation Effects

hg38 • Region Span ~309.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with neuromuscular and skeletal abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859236

Submitter: PanelApp Australia

neurodevelopmental disorder with neuromuscular and skeletal abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859236

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with neuromuscular and skeletal abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859236

Submitter: Ambry Genetics

neurodevelopmental disorder with neuromuscular and skeletal abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859236

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with neuromuscular and skeletal abnormalitiesAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

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: 35108495

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NRCAM variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 181

NRCAM-related disorderTotal: 32

Neurodevelopmental disorder with neuromuscular and skeletal abnormalitiesTotal: 23

not providedTotal: 21

not specifiedTotal: 7

High myopiaTotal: 1

Normal pregnancyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001037132.4. 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				14 clinvar	2 clinvar	16
missense	4 clinvar	1 clinvar	198 clinvar	7 clinvar	1 clinvar	211
nonsense	3 clinvar	1 clinvar	2 clinvar			6
start loss						0
frameshift	2 clinvar	3 clinvar				5
splice donor/acceptor (+/-2bp)		2 clinvar	1 clinvar			3
Total	9	7	201	21	3	241

Highest pathogenic variant AF is 0.00036187208

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 154 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001037132.4	RefSeq	NP_001032209.1	30	MANE Select
ENST00000379028.8	Ensembl	ENSP00000368314.3	30	MANE Select
NM_001193582.2	RefSeq	NP_001180511.1	28	Standard
NM_001193583.2	RefSeq	NP_001180512.1	27	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
NrCAM interactions
Neurofascin interactions
Interaction between L1 and Ankyrins

Biological Process

angiogenesis
neuron migration
axonogenesis
axonal fasciculation
synapse assembly

Molecular Function

protein binding
ankyrin binding
protein binding involved in heterotypic cell-cell adhesion

Cellular Component

extracellular region
plasma membrane
integral component of plasma membrane
external side of plasma membrane
neuron projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379028
Coding exons: 30
Length: 309094
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.91	566	709	0.798	0.0000372	8526
Missense (PolyPhen)		199	305.32	0.65177		3727
Synonymous	1.35	235	263	0.894	0.0000149	2499
Loss of Function	5.74	18	69.8	0.258	0.00000363	854

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00020	0.000099	rare
East Asian	0.00029	0.00027	rare
Finnish	0.000095	0.000092	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cell adhesion protein that is required for normal responses to cell-cell contacts in brain and in the peripheral nervous system. Plays a role in neurite outgrowth in response to contactin binding. Plays a role in mediating cell-cell contacts between Schwann cells and axons. Plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. Nodes of Ranvier contain clustered sodium channels that are crucial for the saltatory propagation of action potentials along myelinated axons. During development, nodes of Ranvier are formed by the fusion of two heminodes. Required for normal clustering of sodium channels at heminodes; not required for the formation of mature nodes with normal sodium channel clusters. Required, together with GLDN, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier. {ECO:0000250|UniProtKB:Q810U4}.;

Recessive Scores

pRec: 0.251

Intolerance Scores

LoFtool: 0.679
RVIS EVS: -1.37
RVIS percentile EVS: 4.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.744

Gene Damage Prediction

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