# NM_001377142.1(PLCB4):c.21del (p.Phe7fs)

https://sugi.bio/variant/plcb4-p-phe7fs

## Summary

**PLCB4 p.Phe7fs (c.21del)** is classified **Likely pathogenic** in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-23).

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the PLCB4 gene that is considered likely disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PLCB4](https://sugi.bio/atlas/gene/PLCB4/) |
| Protein change (HGVS p.) | p.Phe7fs |
| Coding change (HGVS c.) | c.21del |
| MANE Select transcript | [NM_001377142](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377142) |
| Variant type | Deletion |
| Location | chr20:9307833-9307833 (GRCh38) |
| ClinVar | [VCV3342734](https://www.ncbi.nlm.nih.gov/clinvar/variation/3342734/) |

**All HGVS expressions:** `NC_000020.10:g.9288482del`, `NC_000020.11:g.9307835del`, `NG_032790.2:g.243782del`, `NM_000933.4:c.21del`, `NM_001172646.2:c.21del`, `NM_001377134.2:c.21del`, `NM_001377135.1:c.21del`, `NM_001377136.1:c.21del`, `NM_001377142.1:c.21del`, `NM_001377143.1:c.21del`, `NM_182797.3:c.21del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.324, GERP -0.983, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.509, pLI 0.97247), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 40**, 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.

*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}

**PLCB4** population constraint: LOEUF 0.509, pLI 0.97247, missense-Z 3.2834. *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):

- **auriculocondylar syndrome 2** — Definitive (AD)
- **auriculocondylar syndrome 2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.03, 65% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of PLCB4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

PLCB4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | electronic |
| [PLC beta mediated events](https://reactome.org/content/detail/R-HSA-112043) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** phospholipase C-activating endothelin receptor signaling pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-23 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PLCB4 variant pages (same residue, condition, or type): [PLCB4 p.Glu1011fs](/variant/plcb4-p-glu1011fs), [PLCB4 p.Ile272fs](/variant/plcb4-p-ile272fs), [PLCB4 p.Lys1078fs](/variant/plcb4-p-lys1078fs), [PLCB4 c.2525-8del](/variant/plcb4-c-2525-minus-8del), [PLCB4 c.3409-27del](/variant/plcb4-c-3409-minus-27del), [PLCB4 c.3409-6_3409-5del](/variant/plcb4-c-3409-minus-6-3409-minus-5del), [PLCB4 c.3409-7_3409-5del](/variant/plcb4-c-3409-minus-7-3409-minus-5del), [PLCB4 c.1648-279_2051+1546del](/variant/plcb4-c-1648-minus-279-2051-plus-1546del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3342734). 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.*