LMNB2

Chr 19ARAD

lamin B2

Also known as: EPM9, LAMB2, LMN2, MCPH27

NCBI Gene: 84823 ENSG00000176619 UniProt: Q03252 OMIM: 150341

This gene encodes lamin B2, an intermediate filament protein that forms the nuclear lamina meshwork on the inner nuclear membrane and plays essential roles in nuclear envelope structure, chromatin organization, and gene expression. Mutations cause autosomal dominant primary microcephaly with early onset, progressive myoclonic epilepsy, and contribute to acquired partial lipodystrophy susceptibility. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.104), indicating that complete loss of function is poorly tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a B type nuclear lamin. The nuclear lamina consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Mutations in this gene are associated with acquired partial lipodystrophy. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.103 OMIM phenotypes

Clinical Summary— LMNB2

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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

4 unique Pathogenic / Likely Pathogenic· 312 VUS of 690 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 4.95

OE 0.00 (0.00–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

0.66Z-score

OE missense 0.91 (0.83–0.99)

359 obs / 395.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.10)

0≤0.351.4

Missense OE?0.91 (0.83–0.99)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 0 / 28.5Missense obs/exp: 359 / 395.9Syn Z: -0.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongLMNB2-related primary microcephalyOTHERAD

This gene — mechanism propensity

0.74top 25%

GOF

0.6248th %ile

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.10

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

690 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS312

Likely Benign282

Benign57

Conflicting26

Pathogenic

312

VUS

282

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	3	0	0	4
Likely Pathogenic	0	0	0	0	0
VUS	7	291	14	0	312
Likely Benign	0	30	89	163	282
Benign	0	11	40	6	57
Conflicting	—				26
Total	8	335	143	169	681

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap LMNB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →