MYCN

Chr 2AD

MYCN proto-oncogene, bHLH transcription factor

Also known as: FGLDS1, MODED, MPAPA, MYCNsORF, MYCNsPEP, N-myc, NMYC, ODED

NCBI Gene: 4613 ENSG00000134323 UniProt: P04198 OMIM: 164840

The protein is a basic helix-loop-helix transcription factor that dimerizes with other bHLH proteins to bind DNA and regulate gene transcription. Mutations cause Feingold syndrome 1 and megalencephaly-polydactyly syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.89, LOEUF 0.41), and while amplification is associated with neuroblastomas, germline mutations result in developmental syndromes affecting growth, limbs, and brain size.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the MYC family and encodes a protein with a basic helix-loop-helix (bHLH) domain. This protein is located in the nucleus and must dimerize with another bHLH protein in order to bind DNA. Amplification of this gene is associated with a variety of tumors, most notably neuroblastomas. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.412 OMIM phenotypes

Clinical Summary— MYCN

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Gene-Disease Validity (ClinGen)

megalencephaly-polydactyly syndrome · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — MYCN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.889

Z-score 2.87

OE 0.09 (0.03–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.41Z-score

OE missense 0.75 (0.66–0.84)

181 obs / 242.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.03–0.41)

0≤0.351.4

Missense OE?0.75 (0.66–0.84)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 1 / 11.5Missense obs/exp: 181 / 242.7Syn Z: -1.50

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMYCN-related Feingold syndromeLOFAD

This gene — mechanism propensity

0.3992th %ile

GOF

0.2995th %ile

LOF

0.77top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.41 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFWe conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.1

LOFExpanding the clinical spectrum of MYCN-related Feingold syndrome2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References