SEMA6B

Chr 19AD

semaphorin 6B

Also known as: EPM11, SEM-SEMA-Y, SEM-SEMA-Z, SEMA-VIB, SEMAN, semaZ

NCBI Gene: 10501 ENSG00000167680 UniProt: Q9H3T3 OMIM: 608873

The protein is a transmembrane semaphorin that guides axon development in both peripheral and central nervous systems. Gain-of-function mutations cause progressive myoclonic epilepsy type 11 with autosomal dominant inheritance. The pathogenic mechanism involves abnormal neuronal connectivity due to disrupted axonal guidance signaling.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.461 OMIM phenotype

Clinical Summary— SEMA6B

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Gene-Disease Validity (ClinGen)

progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.46LOEUF

pLI 0.062

Z-score 3.97

OE 0.26 (0.16–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.22Z-score

OE missense 0.70 (0.64–0.77)

310 obs / 441.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.26 (0.16–0.46)

0≤0.351.4

Missense OE0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE1.03

0≤1.21.6

LoF obs/exp: 9 / 34.0Missense obs/exp: 310 / 441.2Syn Z: -0.38

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateSEMA6B-related neurodevelopmental disorderOTHERAD

0.6743th %ile

GOF

0.73top 25%

LOF

0.3940th %ile

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

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNThe initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10PMID:32169168

GOFVariants of SEMA6B have been identified in an increasing number of patients, often presenting with progressive myoclonus epilepsy (PME), and to lesser extent developmental encephalopathy, with or without epilepsy. The exon 17 is mainly involved, with truncating mutations causing the production of abPMID:36719163

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.