# NM_006393.3(NEBL):c.2775C>T (p.Pro925=)

https://sugi.bio/variant/nebl-p-pro925

## Summary

**NEBL p.Pro925= (c.2775C>T)** is classified **Likely benign** in NEBL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-27). Ultra-rare (popmax 0.0281%, afr); Associated with dilated cardiomyopathy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs199887353 · 6 submitters · 1 linked condition · ultra-rare (popmax 0.0281%, afr)

## For patients & families {#patients}

This is a change in the NEBL gene that is classified as likely benign — not considered disease-causing, submitted by 6 submitters, 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.Pro925= |
| Coding change (HGVS c.) | c.2775C>T |
| MANE Select transcript | [NM_006393](https://www.ncbi.nlm.nih.gov/nuccore/NM_006393) |
| dbSNP | [rs199887353](https://www.ncbi.nlm.nih.gov/snp/rs199887353/) |
| Variant type | single nucleotide variant |
| Location | chr10:20787295-20787295 (GRCh38) |
| ClinVar | [VCV227736](https://www.ncbi.nlm.nih.gov/clinvar/variation/227736/) |

**All HGVS expressions:** `LRG_411:g.391893C>T`, `LRG_411t1:c.543C>T`, `LRG_411t2:c.2775C>T`, `NC_000010.10:g.21076224G>A`, `NC_000010.11:g.20787295G>A`, `NG_017092.1:g.391893C>T`, `NM_001173484.2:c.543C>T`, `NM_001377322.1:c.636C>T`, `NM_001377323.1:c.495C>T`, `NM_001377324.1:c.486C>T`, `NM_001377325.1:c.477C>T`, `NM_001377326.1:c.435C>T`, `NM_001377327.1:c.435C>T`, `NM_001377328.1:c.435C>T`, `NM_006393.3:c.2775C>T`, `NM_213569.2:c.543C>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 -1.494, GERP -4.19 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.803**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.99 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0281%** (afr) · FAF95 0.0188% · FAF99 0.0157% · 21/74,852 in the highest group · 189/1,612,436 alleles overall — ultra-rare (popmax 0.0281%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 0.11% | 910 |
| African / African-American (grpmax) | 0.0281% | 3,564 |
| European (non-Finnish) | 0.0132% | 7,559 |
| Admixed American | 0.00668% | 14,976 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,606 |
| South Asian | 0.0033% | 30,261 |

Amish 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}

**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}

Residue **925** lies in the 'linker' region.

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. p.Pro925= falls in the linker region.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-27.

**Submitter consensus:** unanimous (6/6 Likely benign).

**Submission history:** 6 submissions (2015–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-10-24 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2015-06-19 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary dilated cardiomyopathy, not specified, not provided, none provided, AllHighlyPenetrant, Dilated Cardiomyopathy.

## Similar variants {#similar}

Related NEBL variant pages (same residue, condition, or type): [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), [NEBL p.Ala440Asp](/variant/nebl-p-ala440asp).

### 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 227736). 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.*