# NM_006393.3(NEBL):c.2241G>A (p.Ser747=)

https://sugi.bio/variant/nebl-p-ser747

## Summary

**NEBL p.Ser747= (c.2241G>A)** is classified **Uncertain significance** in NEBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). Ultra-rare (popmax 0.0165%, mid); Associated with dilated cardiomyopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs377702958 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the NEBL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to dilated cardiomyopathy.

*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 | 159 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000221/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NEBL](https://sugi.bio/atlas/gene/NEBL/) |
| Protein change (HGVS p.) | p.Ser747= |
| Coding change (HGVS c.) | c.2241G>A |
| MANE Select transcript | [NM_006393](https://www.ncbi.nlm.nih.gov/nuccore/NM_006393) |
| dbSNP | [rs377702958](https://www.ncbi.nlm.nih.gov/snp/rs377702958/) |
| Variant type | single nucleotide variant |
| Location | chr10:20815625-20815625 (GRCh38) |
| ClinVar | [VCV1437610](https://www.ncbi.nlm.nih.gov/clinvar/variation/1437610/) |

**All HGVS expressions:** `LRG_411:g.363563G>A`, `LRG_411t1:c.358-2685G>A`, `NC_000010.10:g.21104554C>T`, `NC_000010.11:g.20815625C>T`, `NG_017092.1:g.363563G>A`, `NM_001173484.2:c.358-2685G>A`, `NM_001377322.1:c.358-2685G>A`, `NM_001377323.1:c.310-2685G>A`, `NM_001377324.1:c.301-2685G>A`, `NM_001377325.1:c.292-2685G>A`, `NM_001377326.1:c.250-2685G>A`, `NM_001377327.1:c.250-2685G>A`, `NM_001377328.1:c.250-2685G>A`, `NM_006393.3:c.2241G>A`, `NM_213569.2:c.358-2685G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.70) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.69, GERP 2.58, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.8**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.70**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.72** (loss), gain 0.02 / loss 0.72. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00728% · FAF99 0.00516% · 1/6,044 in the highest group · 27/1,601,018 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,044 |
| East Asian | 0.0156% | 6,393 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,086 |
| European (non-Finnish) | 0.00145% | 68,737 |
| African / African-American | 0.00134% | 74,558 |

*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}

**NEBL** population constraint: LOEUF 1.036, pLI 3.4176e-21, missense-Z -0.093948; ClinGen dosage — haploinsufficiency 0/3, 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):

- **dilated cardiomyopathy** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.00, 2% of residues very-high.

**1 experimental structure(s)** (PDB): [4F14](https://www.rcsb.org/structure/4F14).

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

*Describes the biological roles of NEBL (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:** NEBL's established molecular role includes tropomyosin binding.


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

**Molecular function:** tropomyosin binding, cytoskeletal protein binding, filamin binding, actin filament binding.

**Biological process:** cardiac muscle thin filament assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-27.

**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 | 2025-09-27 |

## Associated conditions {#conditions}

[dilated cardiomyopathy](https://sugi.bio/atlas/disease/dilated-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Primary dilated cardiomyopathy, Dilated Cardiomyopathy.

## Similar variants {#similar}

Related NEBL variant pages (same residue, condition, or type): [NEBL p.Ser747Leu](/variant/nebl-p-ser747leu), [NEBL c.1227+5G>A](/variant/nebl-c-1227-plus-5g-a), [NEBL c.1870-1G>A](/variant/nebl-c-1870-minus-1g-a), [NEBL c.798+1G>A](/variant/nebl-c-798-plus-1g-a), [NEBL c.903+1G>T](/variant/nebl-c-903-plus-1g-t), [NEBL p.Ala114Ser](/variant/nebl-p-ala114ser), [NEBL p.Ala219Thr](/variant/nebl-p-ala219thr), [NEBL p.Ala264Val](/variant/nebl-p-ala264val).

### 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 1437610). 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.*