# NM_022132.5(MCCC2):c.1674del (p.Phe558fs)

https://sugi.bio/variant/mccc2-p-phe558fs

## Summary

**MCCC2 p.Phe558fs (c.1674del)** is classified **Uncertain significance** in MCCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). No gnomAD frequency available for this variant; Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1747594910 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MCCC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to 3-methylcrotonyl-CoA carboxylase 2 deficiency.

*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 recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MCCC2 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of 3-methylcrotonyl-CoA carboxylase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Organic aciduria — Very frequent (99-80%)
- Abnormality of leucine metabolism — Very frequent (99-80%)
- Failure to thrive in infancy — Frequent (79-30%)
- Hyperammonemia — Frequent (79-30%)
- Abnormality of movement — Frequent (79-30%)
- Spasticity — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009151/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MCCC2](https://sugi.bio/atlas/gene/MCCC2/) |
| Protein change (HGVS p.) | p.Phe558fs |
| Coding change (HGVS c.) | c.1674del |
| MANE Select transcript | [NM_022132](https://www.ncbi.nlm.nih.gov/nuccore/NM_022132) |
| dbSNP | [rs1747594910](https://www.ncbi.nlm.nih.gov/snp/rs1747594910/) |
| Variant type | Deletion |
| Location | chr5:71656842-71656842 (GRCh38) |
| ClinVar | [VCV1036862](https://www.ncbi.nlm.nih.gov/clinvar/variation/1036862/) |

**All HGVS expressions:** `NC_000005.10:g.71656842del`, `NC_000005.9:g.70952669del`, `NG_008882.1:g.74555del`, `NM_001363147.1:c.1560del`, `NM_022132.5:c.1674del`

## 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 7.828, GERP 1.53, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.832, pLI 1.8706e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (17 of 17)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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}

**MCCC2** population constraint: LOEUF 0.832, pLI 1.8706e-10, missense-Z 0.45938. *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):

- **3-methylcrotonyl-CoA carboxylase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.82, 93% of residues very-high.

**14 experimental structure(s)** (PDB): [8J4Z](https://www.rcsb.org/structure/8J4Z), [8J73](https://www.rcsb.org/structure/8J73), [8J78](https://www.rcsb.org/structure/8J78), [8J7D](https://www.rcsb.org/structure/8J7D), [8J99](https://www.rcsb.org/structure/8J99), [8JAK](https://www.rcsb.org/structure/8JAK).

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

*Describes the biological roles of MCCC2 (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:** MCCC2 participates in disease-associated pathways. In Reactome, MCCC2 is annotated in disease pathway(s) including **3-Methylcrotonyl-CoA carboxylase deficiency**, **Defective HLCS causes multiple carboxylase deficiency**.

**Disease mechanism (Reactome):** MCCC2 loss or alteration is curated in [3-Methylcrotonyl-CoA carboxylase deficiency](https://reactome.org/content/detail/R-HSA-9909438), [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599).

### Pathways affected {#pathways}

MCCC2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [3-Methylcrotonyl-CoA carboxylase deficiency](https://reactome.org/content/detail/R-HSA-9909438) | other |
| ⚕ [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599) | other |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | other |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | other |

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

**Biological process:** L-leucine catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-27.

**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 | 2021-08-27 |

## Associated conditions {#conditions}

[3-methylcrotonyl-CoA carboxylase 2 deficiency](https://sugi.bio/atlas/disease/3-methylcrotonyl-coa-carboxylase-2-deficiency/).

**Reported phenotype names (ClinVar):** 3-methylcrotonyl-CoA carboxylase 2 deficiency, METHYLCROTONYLGLYCINURIA, TYPE II, 3 alpha methylcrotonyl-CoA carboxylase 2 deficiency, 3 alpha methylcrotonylglycinuria 2, MCC 2 deficiency, Methylcrotonylglycinuria type 2.

## Similar variants {#similar}

Related MCCC2 variant pages (same residue, condition, or type): [MCCC2 p.Phe558=](/variant/mccc2-p-phe558), [MCCC2 p.Phe558Leu](/variant/mccc2-p-phe558leu), [MCCC2 c.1151del](/variant/mccc2-c-1151del), [MCCC2 c.281+1del](/variant/mccc2-c-281-plus-1del), [MCCC2 c.383+2del](/variant/mccc2-c-383-plus-2del), [MCCC2 c.739del](/variant/mccc2-c-739del), [MCCC2 p.Asn230fs](/variant/mccc2-p-asn230fs), [MCCC2 p.Gly118del](/variant/mccc2-p-gly118del).

### 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 1036862). 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.*