# NM_005869.4(CWC27):c.252+4del

https://sugi.bio/variant/cwc27-c-252-plus-4del

## Summary

**CWC27 c.252+4del** is classified **Uncertain significance** in CWC27 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-18). Very rare (popmax 0.00883%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1200215248 · 1 submitter · very rare (popmax 0.00883%, afr)

## For patients & families {#patients}

This is a change in the CWC27 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CWC27](https://sugi.bio/atlas/gene/CWC27/) |
| Coding change (HGVS c.) | c.252+4del |
| MANE Select transcript | [NM_005869](https://www.ncbi.nlm.nih.gov/nuccore/NM_005869) |
| dbSNP | [rs1200215248](https://www.ncbi.nlm.nih.gov/snp/rs1200215248/) |
| Variant type | Deletion |
| Location | chr5:64782036-64782036 (GRCh38) |
| ClinVar | [VCV1063203](https://www.ncbi.nlm.nih.gov/clinvar/variation/1063203/) |

**All HGVS expressions:** `NC_000005.10:g.64782037del`, `NC_000005.9:g.64077864del`, `NM_001297644.1:c.252+4del`, `NM_001297645.2:c.252+4del`, `NM_001318000.2:c.252+4del`, `NM_001364478.1:c.252+4del`, `NM_005869.4:c.252+4del`

## 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 7.702, GERP 5.3, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.82**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Splice region: **donor splice region (+4, within the first 6 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 2.19**, o/e 0.80 (1 kb window 64,782,000–64,783,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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 (gnomAD v4.1): grpmax **0.00883%** (afr) · FAF95 0.00377% · FAF99 0.00258% · 6/67,924 in the highest group · 8/1,326,002 alleles overall — very rare (popmax 0.00883%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00883% | 11,321 |
| Finnish (not grpmax-eligible) | 0.00165% | 60,594 |
| European (non-Finnish) | 0.000105% | 950,480 |

*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}

**CWC27** population constraint: LOEUF 1.181, pLI 4.1569e-06, missense-Z 0.75484. *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):

- **metaphyseal chondrodysplasia-retinitis pigmentosa syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.93, 27% of residues very-high.

**9 experimental structure(s)** (PDB): [2HQ6](https://www.rcsb.org/structure/2HQ6), [4R3E](https://www.rcsb.org/structure/4R3E), [5Z56](https://www.rcsb.org/structure/5Z56), [5Z58](https://www.rcsb.org/structure/5Z58), [6FF4](https://www.rcsb.org/structure/6FF4), [6FF7](https://www.rcsb.org/structure/6FF7).

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

*Describes the biological roles of CWC27 (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.*

**How this variant is thought to act:** CWC27 participates in disease-associated pathways. In Reactome, CWC27 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CWC27 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CWC27 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-18.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-18 |

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

## Similar variants {#similar}

Related CWC27 variant pages (same residue, condition, or type): [CWC27 c.249_252+22del](/variant/cwc27-c-249-252-plus-22del), [CWC27 p.Ala356fs](/variant/cwc27-p-ala356fs), [CWC27 p.Asn109fs](/variant/cwc27-p-asn109fs), [CWC27 p.Gly253fs](/variant/cwc27-p-gly253fs), [CWC27 p.Lys334_Val335insTer](/variant/cwc27-p-lys334-val335inster), [CWC27 p.Ser222fs](/variant/cwc27-p-ser222fs), [CWC27 p.Glu470fs](/variant/cwc27-p-glu470fs), [CWC27 c.1257-7del](/variant/cwc27-c-1257-minus-7del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1063203). 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.*