ACTL6B

Chr 7ARAD

actin like 6B

Also known as: ACTL6, BAF53B, DEE76, EIEE76, IDDSSAD, SMARCN2, arpNalpha

NCBI Gene: 51412 ENSG00000077080 UniProt: O94805 OMIM: 612458

ACTL6B encodes a subunit of the neuron-specific BAF chromatin remodeling complex that is essential for neuronal maturation and dendrite development by altering DNA-histone contacts in an ATP-dependent manner. Mutations cause developmental and epileptic encephalopathy or intellectual developmental disorder with severe speech and ambulation defects. The gene shows both autosomal recessive and autosomal dominant inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a subunit of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. This subunit may be involved in the regulation of genes by structural modulation of their chromatin, specifically in the brain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.652 OMIM phenotypes

Clinical Summary— ACTL6B

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.65LOEUF

pLI 0.000

Z-score 3.00

OE 0.39 (0.24–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.27Z-score

OE missense 0.44 (0.38–0.51)

120 obs / 271.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.39 (0.24–0.65)

0≤0.351.4

Missense OE?0.44 (0.38–0.51)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 11 / 28.2Missense obs/exp: 120 / 271.9Syn Z: 0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveACTL6B-related epileptic encephalopathy, early infantileLOFAR

limitedACTL6B-related intellectual developmental disorder with severe speech and ambulation defectsOTHERAD

This gene — mechanism propensity

0.74top 25%

GOF

0.6834th %ile

LOF

0.3356th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-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 gain-of-function. 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

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

GOFAssessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function.1

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

References