# NM_139343.3(BIN1):c.1464C>T (p.Ser488=)

https://sugi.bio/variant/bin1-p-ser488

## Summary

**BIN1 p.Ser488= (c.1464C>T)** is classified **Likely benign** in BIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). Very rare (popmax 0.00127%, nfe); Associated with myopathy, centronuclear, 2.

**At a glance:** Likely benign · review: Single submitter · rsID rs759941022 · 1 submitter · 1 linked condition · very rare (popmax 0.00127%, nfe)

## For patients & families {#patients}

This is a change in the BIN1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to myopathy, centronuclear, 2.

*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) | Childhood, Infancy, Neonatal |
| Diagnostic panels | BIN1 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Autosomal recessive centronuclear myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- High palate — Frequent (79-30%)
- Retrognathia — Frequent (79-30%)
- Motor delay — Frequent (79-30%)
- Generalized hypotonia — Frequent (79-30%)
- Respiratory insufficiency — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Progressive muscle weakness — Frequent (79-30%)
- Gowers sign — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015208/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BIN1](https://sugi.bio/atlas/gene/BIN1/) |
| Protein change (HGVS p.) | p.Ser488= |
| Coding change (HGVS c.) | c.1464C>T |
| MANE Select transcript | [NM_139343](https://www.ncbi.nlm.nih.gov/nuccore/NM_139343) |
| dbSNP | [rs759941022](https://www.ncbi.nlm.nih.gov/snp/rs759941022/) |
| Variant type | single nucleotide variant |
| Location | chr2:127050910-127050910 (GRCh38) |
| ClinVar | [VCV1138964](https://www.ncbi.nlm.nih.gov/clinvar/variation/1138964/) |

**All HGVS expressions:** `LRG_873:g.61379C>T`, `LRG_873t1:c.1464C>T`, `NC_000002.11:g.127808486G>A`, `NC_000002.12:g.127050910G>A`, `NG_012042.1:g.61379C>T`, `NM_001320632.2:c.957C>T`, `NM_001320633.2:c.1095C>T`, `NM_001320634.1:c.840C>T`, `NM_001320640.2:c.1224C>T`, `NM_001320641.2:c.1371C>T`, `NM_001320642.1:c.1383C>T`, `NM_004305.4:c.1047C>T`, `NM_139343.3:c.1464C>T`, `NM_139344.3:c.1335C>T`, `NM_139345.3:c.1203C>T`, `NM_139346.3:c.1176C>T`, `NM_139347.3:c.1239C>T`, `NM_139348.3:c.1131C>T`, `NM_139349.3:c.1110C>T`, `NM_139350.3:c.1002C>T`, `NM_139351.3:c.912C>T`

## 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 4.372, GERP -0.145, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.33**. 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.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, G>C, IS in the release and scores Δ0.24 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00127%** (nfe) · FAF95 0.000763% · FAF99 0.000605% · 15/1,179,948 in the highest group · 16/1,613,806 alleles overall — very rare (popmax 0.00127%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| European (non-Finnish) (grpmax) | 0.00127% | 78,663 |

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}

**BIN1** population constraint: LOEUF 0.817, pLI 1.3843e-11, missense-Z 1.3433; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **centronuclear myopathy** — Definitive (AR)
- **centronuclear myopathy** — Limited (AD)

## Protein context {#protein}

Residue **488** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.61, 38% of residues very-high.

**7 experimental structure(s)** (PDB): [1MUZ](https://www.rcsb.org/structure/1MUZ), [1MV0](https://www.rcsb.org/structure/1MV0), [1MV3](https://www.rcsb.org/structure/1MV3), [2FIC](https://www.rcsb.org/structure/2FIC), [2RMY](https://www.rcsb.org/structure/2RMY), [2RND](https://www.rcsb.org/structure/2RND).

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

*Describes the biological roles of BIN1 (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:** BIN1's established molecular role includes protease binding. p.Ser488= falls in the disordered region.


### Pathways affected {#pathways}

BIN1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |

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

**Molecular function:** protease binding, lipid binding, aspartic-type endopeptidase inhibitor activity, identical protein binding, tau protein binding, actin filament binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, nucleus organization, endosome to lysosome transport, regulation of cell cycle process, T-tubule organization, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-15 |

## Associated conditions {#conditions}

[myopathy, centronuclear, 2](https://sugi.bio/atlas/disease/myopathy-centronuclear-2/).

**Reported phenotype names (ClinVar):** Myopathy, centronuclear, 2, MYOTUBULAR MYOPATHY, AUTOSOMAL RECESSIVE.

## Similar variants {#similar}

Related BIN1 variant pages (same residue, condition, or type): [BIN1 p.Arg145Cys](/variant/bin1-p-arg145cys), [BIN1 p.Arg234Cys](/variant/bin1-p-arg234cys), [BIN1 c.165+6T>C](/variant/bin1-c-165-plus-6t-c), [BIN1 c.-163T>C](/variant/bin1-c-minus-163t-c), [BIN1 p.Ala104Ser](/variant/bin1-p-ala104ser), [BIN1 p.Ala289Thr](/variant/bin1-p-ala289thr), [BIN1 p.Ala289Val](/variant/bin1-p-ala289val), [BIN1 p.Ala322Val](/variant/bin1-p-ala322val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1138964). 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.*