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

This gene encodes a member of the semaphorin family, a group of proteins characterized by the presence of a conserved semaphorin (sema) domain. Whereas some semaphorins are transmembrane proteins, others are secreted. Semaphorins play a major role in axon guidance. The protein encoded by this gene may be involved in both peripheral and central nervous system development. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 217 VUS of 350 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.26 (0.16–0.46)

0≤0.351.4

Missense OE?0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE?1.03

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

This gene — mechanism propensity

0.6743th %ile

GOF

0.73top 25%

LOF

0.3940th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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

LOF85% of P/LP variants are LoF · LOEUF 0.46

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 × 101

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 ab2

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

References

ClinVar Variant Classifications

350 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic17

VUS217

Likely Benign74

Benign13

Conflicting4

Pathogenic

Likely Pathogenic

217

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	0	0	0	10
Likely Pathogenic	13	4	0	0	17
VUS	13	198	5	1	217
Likely Benign	0	43	1	30	74
Benign	0	3	6	4	13
Conflicting	—				4
Total	36	248	12	35	335

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap SEMA6B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →