GeneBe

RAPSN

protein-coding

receptor associated protein of the synapse, the group of Ring finger proteins

Gene summary

This gene encodes a member of a family of proteins that are receptor associated proteins of the synapse. The encoded protein contains a conserved cAMP-dependent protein kinase phosphorylation site, and plays a critical role in clustering and anchoring nicotinic acetylcholine receptors at synaptic sites by linking the receptors to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin. Mutations in this gene may play a role in postsynaptic congenital myasthenic syndromes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2011]

MANE transcript

NM_005055.5

Inheritance

AR

ClinVar variants

P:151U:232B:227

Top phenotype

Myasthenic syndrome, congenital 11, associated with acetylcholine receptor deficiency

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr11:47,437,764-47,449,143

External References & Databases

Ensembl (ENSG00000165917)NCBI Gene (5913)OMIM (601592)HGNC:9863GenCCUniProt (Q13702)AlphaFoldClinVar (RAPSN)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fetal akinesia deformation sequence 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100101

Submitter: Orphanet

congenital myasthenic syndrome 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014588

Submitter: PanelApp Australia

fetal akinesia deformation sequence 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100102

Submitter: G2P

neuromuscular diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019056

Submitter: Ambry Genetics

congenital myasthenic syndrome 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014588

Submitter: Labcorp Genetics (formerly Invitae)

congenital myasthenic syndrome 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014588

Submitter: Genomics England PanelApp

fetal akinesia deformation sequence 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100102

Submitter: Labcorp Genetics (formerly Invitae)

fetal akinesia deformation sequence 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100102

Submitter: PanelApp Australia

congenital myasthenic syndrome 11DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014588

Submitter: Natera

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital 11, associated with acetylcholine receptor deficiencyAR

Manifestation: Musculoskeletal; Neurologic

Intervention: Musculoskeletal; Neurologic; Pharmacogenomic

Rationale: Prophylactic medications (anticholinesterase therapy) in order to prevent apneic episodes/sudden respiratory insufficiency secondary to fever/infections can be effective; Most individuals with CMS benefit from AChE inhibitors and/or potassium channel blocker 3,4-diaminopyridine (3,4-DAP), though caution must be used in giving 3,4-DAP to young children and individuals with fast-channel syndromes; Some individuals with SCCMS are treated with quinidine, which has some major side effects and may be detrimental in individuals with AChR deficiency

Refs: 12651869; 14504330; 15286164; 18179903; 18252226; 19261599; 20930056; 25194721; 25792100Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAPSN variants in ClinVar

14 Conditions Cataloged
Congenital myasthenic syndrome 11Total: 605
Fetal akinesia deformation sequence 1Total: 585
Congenital myasthenic syndromeTotal: 173
not providedTotal: 125
Fetal akinesia deformation sequence 2Total: 85
RAPSN-related disorderTotal: 75
Inborn genetic diseasesTotal: 65
not specifiedTotal: 34

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005055.5. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
215
clinvar
1
clinvar
 225
missense
3
clinvar
25
clinvar
219
clinvar
10
clinvar
1
clinvar
 258
nonsense
24
clinvar
12
clinvar
2
clinvar
 38
start loss
1
clinvar
1
clinvar
 2
frameshift
41
clinvar
25
clinvar
1
clinvar
 67
splice donor/acceptor (+/-2bp)
5
clinvar
14
clinvar
1
clinvar
 20
Total74772322252610

Highest pathogenic variant AF is 0.002027891

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005055.5RefSeqNP_005046.28MANE Select
ENST00000298854.7EnsemblENSP00000298854.28MANE Select
NM_001440490.1RefSeqNP_001427419.18Standard
NM_001440491.1RefSeqNP_001427420.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
rapsnDanio rerio

Structure: CaP motoneuron

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • role of nicotinic acetylcholine receptors in the regulation of apoptosis
  • agrin in postsynaptic differentiation

Biological Process

  • chemical synaptic transmission
  • synaptic transmission, cholinergic
  • positive regulation of neuron apoptotic process
  • positive regulation of neuromuscular synaptic transmission
  • regulation of postsynaptic membrane organization

Molecular Function

  • acetylcholine receptor binding
  • ionotropic glutamate receptor binding
  • protein membrane anchor
  • metal ion binding

Cellular Component

  • Golgi apparatus
  • centrosome
  • cytosol
  • plasma membrane
  • cell junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000298854
Coding exons
8
Length
11423
Individuals with no LoFs
125725
Homozygous LoFs
0
Heterozygous LoFs
16
Defined
125741
p
0.0000636
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5482332580.9040.00001762672
Missense (PolyPhen)8590.8590.93552899
Synonymous0.06381121130.9920.00000825783
Loss of Function2.41819.50.4118.43e-7221

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000330.00016rare
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. It may link the receptor to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin.;
Disease
DISEASE: Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency (CMS11) [MIM:616326]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS11 is an autosomal recessive disorder of postsynaptic neuromuscular transmission, due to deficiency of AChR at the endplate that results in low amplitude of the miniature endplate potential and current. {ECO:0000269|PubMed:11791205, ECO:0000269|PubMed:12730725, ECO:0000269|PubMed:12796535, ECO:0000269|PubMed:12929188, ECO:0000269|PubMed:14504330, ECO:0000269|PubMed:15036330, ECO:0000269|PubMed:15328566, ECO:0000269|PubMed:16931511, ECO:0000269|PubMed:17594401}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fetal akinesia deformation sequence (FADS) [MIM:208150]: A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. {ECO:0000269|PubMed:18179903, ECO:0000269|PubMed:18252226}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.256
RVIS EVS
0.22
RVIS percentile EVS
68.38

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.724

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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