ACTB

Chr 7AD

actin beta

Also known as: BKRNS, BNS, BRWS1, CSMH, DDS1, PS1TP5BP1, THC8

NCBI Gene: 60 ENSG00000075624 UniProt: P60709

This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]

Primary Disease Associations & Inheritance

Baraitser-Winter syndrome 1MIM #243310

Becker nevus, syndromic or isolated, somatic mosaicMIM #604919

Congenital smooth muscle hamartoma with or without hemihypertrophy, somatic mosaicMIM #620470

Dystonia-deafness syndrome 1MIM #607371

Thrombocytopenia 8, with dysmorphic features and developmental delayMIM #620475

UniProtBecker nevus syndrome

586

ClinVar variants

135

Pathogenic / LP

0.99

pLI score· haploinsufficient

Active trials

Clinical Summary— ACTB

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Gene-Disease Validity (ClinGen)

Baraitser-Winter cerebrofrontofacial syndrome · 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 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

135 Pathogenic / Likely Pathogenic· 153 VUS of 586 total submissions

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Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.23LOEUF

pLI 0.986

Z-score 3.32

OE 0.00 (0.00–0.23)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

5.02Z-score

OE missense 0.06 (0.04–0.10)

14 obs / 226.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.23)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.06 (0.04–0.10)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.96

0≤1.21.6

LoF obs/exp: 0 / 12.9Missense obs/exp: 14 / 226.7Syn Z: -7.44

ClinVar Variant Classifications

586 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57

Likely Pathogenic78

VUS153

Likely Benign270

Benign11

Conflicting17

Pathogenic

Likely Pathogenic

153

VUS

270

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	20	29	0	57
Likely Pathogenic	7	58	13	0	78
VUS	6	114	28	5	153
Likely Benign	0	0	94	176	270
Benign	0	0	7	4	11
Conflicting	—				17
Total	21	192	171	185	586

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

View in ClinVar →

Protein Context — Lollipop Plot

ACTB · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ACTB-related haploinsufficiency syndrome

strong

ADLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

ACTB-related Baraitser-Winter syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersEye

G2P ↗

missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

ACTIN, BETA; ACTB

MIM #102630 · *

Baraitser-Winter syndrome 1

MIM #243310