GeneBe

PRRT2

protein-coding

proline rich transmembrane protein 2, the group of interferon induced transmembrane protein domain containing

Gene summary

This gene encodes a transmembrane protein containing a proline-rich domain in its N-terminal half. Studies in mice suggest that it is predominantly expressed in brain and spinal cord in embryonic and postnatal stages. Mutations in this gene are associated with episodic kinesigenic dyskinesia-1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Previous symbols:
  • ICCA
  • DYT10

MANE transcript

NM_145239.3

Inheritance

AD, AR

ClinVar variants

P:169U:313B:185

Top phenotype

Episodic kinesigenic dyskinesia 1

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr16:29,811,382-29,815,892

External References & Databases

Ensembl (ENSG00000167371)NCBI Gene (112476)OMIM (614386)HGNC:30500GenCCUniProt (Q7Z6L0)AlphaFoldClinVar (PRRT2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~4.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

seizures, benign familial infantile, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011593

Submitter: Genomics England PanelApp

PRRT2-associated paroxysmal movement disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100556

Submitter: PanelApp Australia

PRRT2-associated paroxysmal movement disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100556

Submitter: PanelApp Australia

infantile convulsions and choreoathetosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011178

Submitter: G2P

infantile convulsions and choreoathetosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011178

Submitter: ClinGen

PRRT2 encompasses a variety of phenotypes including benign familial infantile seizures (BFIE) and paroxysmal kinesigenic choreoathetosis (PKC). BFIE commonly present between 3 and 12 months of age, carry good response to medication, with seizures remitting by 18 months. PKC is characterized by recurrent and/or brief attacks of involuntary movement characterized by chorea, athetosis and/or other dystonic features, triggered by voluntary movement, with typical onset in childhood through adolescence and gradual reduction in severity and frequency with age. These features (BFIE and PKC) have been documented to occur in the same individuals; the presence of both of these phenotypes is identified as infantile convulsions and paroxysmal choreoathetosis (ICCA). Loss of function variants have been primarily reported in association with this gene and phenotypes, (most notably the recurrent p.Arg217Profs*8 (c.649dupC) variant) and segregate with disease in several different families in the literature (selected publications- PMID:22101681, 22243967, 22870186, 29215089). Evidence supporting this gene disease pair includes case level and experimental data. Supporting experimental evidence has been reported in mice and rat studies (selected publications- PMID:22101681, 22243967, 27172900). This association between gene and disease has been maintained over time. Of note, instances of individuals have been reported with these phenotypes together and in isolation. Given the age dependent nature of these presentations, it is possible that the manifestations of these features may be separated by many years; initial reporting of individuals with only one of the phenotypes may be a result of age at time of report. In summary, PRRT2 is definitively associated with autosomal dominant infantile convulsions and paroxysmal choreoathetosis (ICCA). This has been demonstrated in both research and clinical settings.

episodic kinesigenic dyskinesia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100352

Submitter: Labcorp Genetics (formerly Invitae)

PRRT2-associated paroxysmal movement disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100556

Submitter: Ambry Genetics

neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

familial or sporadic hemiplegic migraineSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018925

Submitter: Orphanet

infantile convulsions and choreoathetosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011178

Submitter: Genomics England PanelApp

episodic kinesigenic dyskinesia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007494

Submitter: Genomics England PanelApp

childhood onset GLUT1 deficiency syndrome 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012805

Submitter: Orphanet

benign familial infantile epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017615

Submitter: Orphanet

episodic kinesigenic dyskinesia 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007494

Submitter: Orphanet

paroxysmal nonkinesigenic dyskinesia 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007326

Submitter: Orphanet

seizures, benign familial infantile, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011593

Submitter: Labcorp Genetics (formerly Invitae)

hereditary neurological diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100545

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Episodic kinesigenic dyskinesia 1AD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: In Episodic kinesigenic dyskinesia, treatment with carbamazepine has been shown to particularly effective in affected individuals

Comments: As with other disorders that manifest with seizures, maximal seizure control is beneficial

Refs: 22101681; 22120146; 22243967; 22543779; 22832103; 22870186; 23535490; 28331464Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRRT2 variants in ClinVar

29 Conditions Cataloged
Episodic kinesigenic dyskinesiaTotal: 558
not providedTotal: 231
Inborn genetic diseasesTotal: 93
not specifiedTotal: 70
Episodic kinesigenic dyskinesia 1Total: 53
Seizures, benign familial infantile, 2Total: 50
Infantile convulsions and choreoathetosisTotal: 43
PRRT2-Related DisorderTotal: 43

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145239.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
130
clinvar
 133
missense
4
clinvar
25
clinvar
303
clinvar
51
clinvar
3
clinvar
 386
nonsense
26
clinvar
5
clinvar
 31
start loss
2
clinvar
 2
frameshift
72
clinvar
29
clinvar
1
clinvar
 102
splice donor/acceptor (+/-2bp)
5
clinvar
2
clinvar
5
clinvar
1
clinvar
 13
Total107623131823667

Highest pathogenic variant AF is 0.0017387591

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_145239.3RefSeqNP_660282.23MANE Select
ENST00000358758.12EnsemblENSP00000351608.73MANE Select
NM_001256442.2RefSeqNP_001243371.12Standard
NM_001256443.2RefSeqNP_001243372.11Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • synaptic vesicle fusion to presynaptic active zone membrane
  • negative regulation of SNARE complex assembly
  • neuromuscular process controlling posture
  • negative regulation of short-term synaptic potentiation

Molecular Function

  • syntaxin-1 binding

Cellular Component

  • plasma membrane
  • synaptic vesicle
  • postsynaptic density
  • membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000567659
Coding exons
2
Length
4025
Individuals with no LoFs
125675
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125680
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2252132220.9570.00001152477
Missense (PolyPhen)6174.5520.81823842
Synonymous-0.002639595.01.000.00000529904
Loss of Function2.55211.20.1786.83e-7119

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000630.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000560.000054rare
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian0.0000990.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: As a component of the outer core of AMPAR complex, may be involved in synaptic transmission in the central nervous system. In hippocampal neurons, in presynaptic terminals, plays an important role in the final steps of neurotransmitter release, possibly by regulating Ca(2+)-sensing. In the cerebellum, may inhibit SNARE complex formation and downregulate short-term facilitation. {ECO:0000250|UniProtKB:E9PUL5}.;
Disease
DISEASE: Episodic kinesigenic dyskinesia 1 (EKD1) [MIM:128200]: An autosomal dominant neurologic condition characterized by recurrent and brief attacks of abnormal involuntary movements, triggered by sudden voluntary movement. These attacks usually have onset during childhood or early adulthood and can involve dystonic postures, chorea, or athetosis. {ECO:0000269|PubMed:22101681, ECO:0000269|PubMed:22120146, ECO:0000269|PubMed:22131361, ECO:0000269|PubMed:22209761, ECO:0000269|PubMed:25915028, ECO:0000269|PubMed:27172900}. Note=The disease is caused by mutations affecting the gene represented in this entry. Disease- causing mutations that produce truncation of the C-terminus of the protein alter subcellular location, from plasma membrane to cytoplasm (PubMed:22101681). {ECO:0000269|PubMed:22101681}.; DISEASE: Convulsions, familial infantile, with paroxysmal choreoathetosis (ICCA) [MIM:602066]: A syndrome characterized by clinical features of benign familial infantile seizures and episodic kinesigenic dyskinesia. Benign familial infantile seizures is a disorder characterized by afebrile seizures occurring during the first year of life, without neurologic sequelae. Paroxysmal choreoathetosis is a disorder of involuntary movements characterized by attacks that occur spontaneously or are induced by a variety of stimuli. {ECO:0000269|PubMed:22243967, ECO:0000269|PubMed:22832103}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Seizures, benign familial infantile, 2 (BFIS2) [MIM:605751]: A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS2 inheritance is autosomal dominant. {ECO:0000269|PubMed:22243967, ECO:0000269|PubMed:22399141, ECO:0000269|PubMed:22623405}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0808

Intolerance Scores

LoFtool
0.475
RVIS EVS
0.55
RVIS percentile EVS
81.38

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.896

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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