CELF2

Chr 10AD

CUGBP Elav-like family member 2

Also known as: BRUNOL3, CELF-2, CUG-BP2, CUGBP2, DEE97, ETR-3, ETR3, NAPOR

NCBI Gene: 10659 ENSG00000048740 UniProt: O95319 OMIM: 602538

CELF2 encodes an RNA-binding protein that regulates pre-mRNA alternative splicing, mRNA stability, and translation through binding to UG-rich sequences and other RNA motifs. Mutations cause developmental and epileptic encephalopathy 97, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI = 1.00, LOEUF = 0.174), consistent with its critical role in neurodevelopment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Members of the CELF/BRUNOL protein family contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing, and translation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 97MIM #619561

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Developmental and epileptic encephalopathy 97; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.17

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 4.66

OE 0.04 (0.01–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.34Z-score

OE missense 0.29 (0.25–0.35)

88 obs / 298.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.29 (0.25–0.35)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 1 / 27.2Missense obs/exp: 88 / 298.9Syn Z: -0.45

Background carrier burden — how many people carry a rare variant somewhere in CELF2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 230

427 rare PASS variants

Rare truncating (LoF)

1 in 4,100

37 rare PASS variants

Rare synonymous (reference)

1 in 140

301 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CELF2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 220	1 in 3,900
South Asian	~43k	1 in 230	≈ 1 in 13,000
Remaining (unassigned)	~30k	1 in 160	1 in 980
European (Finnish)	~27k	1 in 570	≈ 1 in 6,200
Admixed American	~22k	1 in 140	1 in 1,900
African / African American	~21k	1 in 170	1 in 4,000
East Asian	~20k	1 in 380	1 in 1,400
Ashkenazi Jewish	~13k	1 in 410	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 410	≈ 1 in 2,600

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 13 coding exons well covered in gnomAD exomes; exons 1, 3, 7 marginal. Genomes: all 13.? see exons ↓