MEF2C

Chr 5AD

myocyte enhancer factor 2C

Also known as: C5DELq14.3, DEL5q14.3, NEDHSIL

NCBI Gene: 4208 ENSG00000081189 UniProt: Q06413 OMIM: 600662

MEF2C encodes a transcription factor that regulates muscle-specific gene expression and plays crucial roles in cardiac development, neuronal development, and synaptic transmission in the hippocampus and neocortex. Mutations cause autosomal dominant neurodevelopmental disorder characterized by severe intellectual disability, epilepsy, stereotypic hand movements, hypotonia, and impaired language development. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.608), and deletions encompassing this locus cause chromosome 5q14.3 deletion syndrome with overlapping features.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This locus encodes a member of the MADS box transcription enhancer factor 2 (MEF2) family of proteins, which play a role in myogenesis. The encoded protein, MEF2 polypeptide C, has both trans-activating and DNA binding activities. This protein may play a role in maintaining the differentiated state of muscle cells. Mutations and deletions at this locus have been associated with severe cognitive disability, stereotypic movements, epilepsy, and cerebral malformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Chromosome 5q14.3 deletion syndromeMIM #613443

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageMIM #613443

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2019

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

187

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.61

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — MEF2C

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.61LOEUF

pLI 0.017

Z-score 2.91

OE 0.32 (0.18–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.95Z-score

OE missense 0.34 (0.29–0.40)

96 obs / 283.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.32 (0.18–0.61)

0≤0.351.4

Missense OE?0.34 (0.29–0.40)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 7 / 21.6Missense obs/exp: 96 / 283.2Syn Z: 1.37

Background carrier burden — how many people carry a rare variant somewhere in MEF2C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 680

344 rare PASS variants

Rare truncating (LoF)

1 in 470

40 rare PASS variants

Rare synonymous (reference)

1 in 320

202 rare PASS variants

Rare missense and truncating variants are carried at similar rates in MEF2C; this gene does not show strong loss-of-function constraint by this measure. 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 760	1 in 2,900
South Asian	~43k	1 in 520	1 in 840
Remaining (unassigned)	~30k	1 in 1,000	1 in 950
European (Finnish)	~27k	1 in 1,100	≈ 1 in 27,000
Admixed American	~22k	1 in 510	1 in 2,300
African / African American	~21k	1 in 380	≈ 1 in 21,000
East Asian	~20k	1 in 230	1 in 2,200
Ashkenazi Jewish	~13k	≈ 1 in 6,500	none seen
Middle Eastern	~2,884	≈ 1 in 710	none seen

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.