# NM_145239.3(PRRT2):c.341_342del (p.Val114fs)

https://sugi.bio/variant/prrt2-p-val114fs

## Summary

**PRRT2 p.Val114fs (c.341_342del)** is classified **Likely pathogenic** in PRRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-15). No gnomAD frequency available for this variant; Associated with seizures, benign familial infantile, 2.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1900077598 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PRRT2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to seizures, benign familial infantile, 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | PRRT2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Self-limited infantile epilepsy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Normal interictal EEG — Very frequent (99-80%)
- Neonatal seizure — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Choreoathetosis — Frequent (79-30%)
- Dystonia — Frequent (79-30%)
- Chorea — Frequent (79-30%)
- Apnea — Frequent (79-30%)
- Focal clonic seizure — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016504/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRRT2](https://sugi.bio/atlas/gene/PRRT2/) |
| Protein change (HGVS p.) | p.Val114fs |
| Coding change (HGVS c.) | c.341_342del |
| MANE Select transcript | [NM_145239](https://www.ncbi.nlm.nih.gov/nuccore/NM_145239) |
| dbSNP | [rs1900077598](https://www.ncbi.nlm.nih.gov/snp/rs1900077598/) |
| Variant type | Deletion |
| Location | chr16:29813394-29813395 (GRCh38) |
| ClinVar | [VCV976325](https://www.ncbi.nlm.nih.gov/clinvar/variation/976325/) |

**All HGVS expressions:** `NC_000016.10:g.29813395_29813396del`, `NC_000016.9:g.29824716_29824717del`, `NG_032039.1:g.6308_6309del`, `NM_001256442.2:c.341_342del`, `NM_001256443.2:c.341_342del`, `NM_145239.3:c.341_342del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.13, GERP -2.59, phastCons 0.964 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PRRT2** population constraint: LOEUF 0.633, pLI 0.65632, missense-Z -0.24908; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **infantile convulsions and choreoathetosis** — Definitive (AD)

## Protein context {#protein}

Residue **114** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 51.86, 0% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-15.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-05-15 |

## Associated conditions {#conditions}

[seizures, benign familial infantile, 2](https://sugi.bio/atlas/disease/seizures-benign-familial-infantile-2/).

**Reported phenotype names (ClinVar):** Seizures, benign familial infantile, 2, CONVULSIONS, BENIGN FAMILIAL INFANTILE, 2.

## Similar variants {#similar}

Related PRRT2 variant pages (same residue, condition, or type): [PRRT2 p.Arg217fs](/variant/prrt2-p-arg217fs), [PRRT2 p.Leu171_Ser172insTer](/variant/prrt2-p-leu171-ser172inster), [PRRT2 p.Asn98fs](/variant/prrt2-p-asn98fs), [PRRT2 c.-65-1G>A](/variant/prrt2-c-minus-65-minus-1g-a), [PRRT2 p.Cys276Tyr](/variant/prrt2-p-cys276tyr), [PRRT2 c.879+5G>A](/variant/prrt2-c-879-plus-5g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 976325). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*