# NM_017780.4(CHD7):c.5955del (p.Phe1985fs)

https://sugi.bio/variant/chd7-p-phe1985fs

## Summary

**CHD7 p.Phe1985fs (c.5955del)** is classified **Likely pathogenic** in CHD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). No gnomAD frequency available for this variant; Associated with CHARGE syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2488035644 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CHD7 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to CHARGE syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000029/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD7](https://sugi.bio/atlas/gene/CHD7/) |
| Protein change (HGVS p.) | p.Phe1985fs |
| Coding change (HGVS c.) | c.5955del |
| MANE Select transcript | [NM_017780](https://www.ncbi.nlm.nih.gov/nuccore/NM_017780) |
| dbSNP | [rs2488035644](https://www.ncbi.nlm.nih.gov/snp/rs2488035644/) |
| Variant type | Deletion |
| Location | chr8:60852554-60852554 (GRCh38) |
| ClinVar | [VCV2444223](https://www.ncbi.nlm.nih.gov/clinvar/variation/2444223/) |

**All HGVS expressions:** `LRG_176:g.178779del`, `LRG_176t1:c.5955del`, `NC_000008.10:g.61765117del`, `NC_000008.11:g.60852558del`, `NG_007009.1:g.178779del`, `NM_001316690.1:c.1717-9671del`, `NM_017780.4:c.5955del`

## 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 4.246, GERP -0.291, phastCons 0.998 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.109, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 30 of 38**, 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}

**CHD7** population constraint: LOEUF 0.109, pLI 1, missense-Z 3.9606; 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):

- **CHARGE syndrome** — Definitive (AD)

## Protein context {#protein}


**3 experimental structure(s)** (PDB): [2CKC](https://www.rcsb.org/structure/2CKC), [2V0E](https://www.rcsb.org/structure/2V0E), [2V0F](https://www.rcsb.org/structure/2V0F).

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

*Describes the biological roles of CHD7 (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}

CHD7 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |

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

**Biological process:** skeletal system development, in utero embryonic development, heart morphogenesis, central nervous system development, cranial nerve development, T cell differentiation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-02-23 |

## Associated conditions {#conditions}

[CHARGE syndrome](https://sugi.bio/atlas/disease/charge-syndrome/).

**Reported phenotype names (ClinVar):** CHARGE syndrome, Hittner Hirsch Kreh syndrome, Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies, CHARGE association, Hall-Hittner syndrome, CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES.

## Similar variants {#similar}

Related CHD7 variant pages (same residue, condition, or type): [CHD7 c.8078del](/variant/chd7-c-8078del), [CHD7 p.Arg969fs](/variant/chd7-p-arg969fs), [CHD7 p.Asn96fs](/variant/chd7-p-asn96fs), [CHD7 p.Asp1090fs](/variant/chd7-p-asp1090fs), [CHD7 p.Asp2684fs](/variant/chd7-p-asp2684fs), [CHD7 p.Gln2426fs](/variant/chd7-p-gln2426fs), [CHD7 p.Glu2450fs](/variant/chd7-p-glu2450fs), [CHD7 p.His903fs](/variant/chd7-p-his903fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2444223). 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.*