PRRT2

Chr 16AD

proline rich transmembrane protein 2

Also known as: BFIC2, BFIS2, DSPB3, DYT10, EKD1, FICCA, ICCA, IFITMD1

NCBI Gene: 112476 ENSG00000167371 UniProt: Q7Z6L0 OMIM: 614386

The protein is a transmembrane protein with a proline-rich domain that is predominantly expressed in brain and spinal cord during embryonic and postnatal development. Mutations cause autosomal dominant episodic kinesigenic dyskinesia, benign familial infantile seizures, and familial infantile convulsions with paroxysmal choreoathetosis. The pathogenic mechanism involves haploinsufficiency, as suggested by the low LOEUF score indicating intolerance to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.563 OMIM phenotypes

Clinical Summary— PRRT2

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Gene-Disease Validity (ClinGen)

infantile convulsions and choreoathetosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.

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ClinVar Variants

60 unique Pathogenic / Likely Pathogenic· 88 VUS of 199 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRRT2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.56LOEUF

pLI 0.579

Z-score 2.55

OE 0.18 (0.07–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

0.23Z-score

OE missense 0.96 (0.85–1.07)

213 obs / 222.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.18 (0.07–0.56)

0≤0.351.4

Missense OE0.96 (0.85–1.07)

0≤0.61.4

Synonymous OE1.00

0≤1.21.6

LoF obs/exp: 2 / 11.2Missense obs/exp: 213 / 222.5Syn Z: -0.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderatePRRT2-related neurodevelopmental and movement disorder with or without seizuresLOFAR

definitivePRRT2-related paroxysmal kinesigenic dyskinesia with or without benign infantile seizuresLOFAD

0.5280th %ile

GOF

0.6833th %ile

LOF

0.4825th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOF1 literature citation · 42% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFOur studies suggest that PRRT2 frameshift mutation leads to the loss of function by affecting its mRNA stability, a mechanism that is different from haploinsufficiency due to dysfunctional protein or gain of function caused by truncated protein.PMID:31785815

LOFThis is the first report of a short nonsense mutation in PRRT2 and indicates that the manifestations of the disease, including other mutations to date, can be explained by haploinsufficiency and that 1 intact PRRT2 allele can allow normal cognitive development.PMID:30713971

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.