# NM_020549.5(CHAT):c.45del (p.Lys16fs)

https://sugi.bio/variant/chat-p-lys16fs

## Summary

**CHAT p.Lys16fs (c.45del)** is classified **Uncertain significance** in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-18). Very rare (popmax 0.000431%, nfe); Associated with congenital myasthenic syndrome 6.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1838387913 · 1 submitter · 1 linked condition · very rare (popmax 0.000431%, nfe)

## For patients & families {#patients}

This is a change in the CHAT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital myasthenic syndrome 6.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009689/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHAT](https://sugi.bio/atlas/gene/CHAT/) |
| Protein change (HGVS p.) | p.Lys16fs |
| Coding change (HGVS c.) | c.45del |
| MANE Select transcript | [NM_020549](https://www.ncbi.nlm.nih.gov/nuccore/NM_020549) |
| dbSNP | [rs1838387913](https://www.ncbi.nlm.nih.gov/snp/rs1838387913/) |
| Variant type | Deletion |
| Location | chr10:49614229-49614229 (GRCh38) |
| ClinVar | [VCV949501](https://www.ncbi.nlm.nih.gov/clinvar/variation/949501/) |

**All HGVS expressions:** `NC_000010.10:g.50822280del`, `NC_000010.11:g.49614234del`, `NG_011797.1:g.10140del`, `NG_053144.1:g.8934del`, `NM_001142929.2:c.-310del`, `NM_001142933.2:c.-272del`, `NM_001142934.2:c.-380del`, `NM_020549.5:c.45del`, `NM_020984.4:c.-68-2268del`, `NM_020985.4:c.-240-70del`, `NM_020986.4:c.-69+1032del`

## 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 0.537, GERP -3.35, phastCons 0.926 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.973, pLI 9.9145e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 15**, 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.
- Repeat context: **low_complexity** (G-rich). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.000431%** (nfe) · FAF95 0.000115% · FAF99 3.2e-05% · 3/696,184 in the highest group · 5/890,894 alleles overall — very rare (popmax 0.000431%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00515% | 19,420 |
| European (non-Finnish) (grpmax) | 0.000431% | 232,061 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CHAT** population constraint: LOEUF 0.973, pLI 9.9145e-17, missense-Z 0.67235; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **congenital myasthenic syndrome 6** — Definitive (AR)

## Protein context {#protein}

Residue **16** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 84.73, 75% of residues very-high.

**8 experimental structure(s)** (PDB): [2FY2](https://www.rcsb.org/structure/2FY2), [2FY3](https://www.rcsb.org/structure/2FY3), [2FY4](https://www.rcsb.org/structure/2FY4), [2FY5](https://www.rcsb.org/structure/2FY5), [7AMD](https://www.rcsb.org/structure/7AMD), [9F84](https://www.rcsb.org/structure/9F84).

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

*Describes the biological roles of CHAT (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Acetylcholine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-264642) | other |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-18.

**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 | 2022-07-18 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 6](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-6/).

**Reported phenotype names (ClinVar):** Familial infantile myasthenia, MYASTHENIC SYNDROME, PRESYNAPTIC, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA, Congenital myasthenic syndrome type 6, MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC.

## Similar variants {#similar}

Related CHAT variant pages (same residue, condition, or type): [CHAT p.Asp328fs](/variant/chat-p-asp328fs), [CHAT p.Cys453_Glu455delinsTer](/variant/chat-p-cys453-glu455delinster), [CHAT p.Gln223fs](/variant/chat-p-gln223fs), [CHAT p.Gly617fs](/variant/chat-p-gly617fs), [CHAT p.Pro138fs](/variant/chat-p-pro138fs), [CHAT p.Gly2_Leu3insTer](/variant/chat-p-gly2-leu3inster), [SLC18A3 p.Lys16Glu](/variant/slc18a3-p-lys16glu), [CHAT c.1977+1_1977+9del](/variant/chat-c-1977-plus-1-1977-plus-9del).

### 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 949501). 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.*