DNM2

Chr 19ADAR

dynamin 2

Also known as: CMT2M, CMTDI1, CMTDIB, DI-CMTB, DYN2, DYNII, LCCS5

NCBI Gene: 1785 ENSG00000079805 UniProt: P50570 OMIM: 602378

DNM2 encodes dynamins that function as GTP-binding proteins involved in endocytosis and cytoskeletal interactions through self-assembly and GTPase activity. Mutations cause centronuclear myopathy 1, Charcot-Marie-Tooth disease (axonal type 2M and dominant intermediate B), and lethal congenital contracture syndrome 5 through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves loss of function, reflecting the protein's essential role in membrane dynamics and cellular structure.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain. Dynamins are associated with microtubules. They have been implicated in cell processes such as endocytosis and cell motility, and in alterations of the membrane that accompany certain activities such as bone resorption by osteoclasts. Dynamins bind many proteins that bind actin and other cytoskeletal proteins. Dynamins can also self-assemble, a process that stimulates GTPase activity. Five alternatively spliced transcripts encoding different proteins have been described. Additional alternatively spliced transcripts may exist, but their full-length nature has not been determined. [provided by RefSeq, Jun 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.184 OMIM phenotypes

VCEP Guidelines: Congenital MyopathiesReleased

ClinGen Panel

Clinical Summary— DNM2

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

30 unique Pathogenic / Likely Pathogenic· 608 VUS of 1407 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DNM2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 5.66

OE 0.07 (0.03–0.18)

Highly constrained

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

Missense Constraint?

3.48Z-score

OE missense 0.57 (0.52–0.63)

302 obs / 527.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.18)

0≤0.351.4

Missense OE?0.57 (0.52–0.63)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 3 / 43.1Missense obs/exp: 302 / 527.0Syn Z: -2.09

This gene — mechanism propensity

0.5082th %ile

GOF

0.4481th %ile

LOF

0.67top 25%

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 · LOEUF 0.18

GOF1 literature citation · 100% of P/LP are missense

Literature Evidence

GOFGain-of-Function Properties of a Dynamin 2 Mutant Implicated in Charcot-Marie-Tooth Disease1

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

References

1.PMID 34744632 ↗

ClinVar Variant Classifications

1407 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic18

VUS608

Likely Benign601

Benign49

Conflicting81

Pathogenic

Likely Pathogenic

608

VUS

601

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	12	0	0	12
Likely Pathogenic	0	18	0	0	18
VUS	31	497	69	11	608
Likely Benign	0	18	263	320	601
Benign	0	4	41	4	49
Conflicting	—				81
Total	31	549	373	335	1,369

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

13 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap DNM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →