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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

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

64 unique Pathogenic / Likely Pathogenic· 96 VUS of 265 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 →

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 OE?0.18 (0.07–0.56)

0≤0.351.4

Missense OE?0.96 (0.85–1.07)

0≤0.61.4

Synonymous OE?1.00

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

This gene — mechanism propensity

0.5280th %ile

GOF

0.6833th %ile

LOF

0.4825th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 81% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median · 1 literature citation

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.1

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.2

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

References

ClinVar Variant Classifications

265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49

Likely Pathogenic15

VUS96

Likely Benign72

Benign7

Conflicting25

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	42	4	3	0	49
Likely Pathogenic	10	5	0	0	15
VUS	2	92	2	0	96
Likely Benign	0	14	8	50	72
Benign	0	1	5	1	7
Conflicting	—				25
Total	54	116	18	51	264

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

176 pathogenic / likely-pathogenic (of 186) ClinVar copy-number / structural variants overlap PRRT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →