CTNNB1

Chr 3AD

catenin beta 1

Also known as: CTNNB, EVR7, MRD19, NEDSDV, armadillo

NCBI Gene: 1499 ENSG00000168036 UniProt: P35222

The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

Colorectal cancer, somaticMIM #114500

Exudative vitreoretinopathy 7MIM #617572

Hepatocellular carcinoma, somaticMIM #114550

Medulloblastoma, somaticMIM #155255

Neurodevelopmental disorder with spastic diplegia and visual defectsMIM #615075

Ovarian cancer, somaticMIM #167000

Pilomatricoma, somaticMIM #132600

UniProtPilomatrixoma

UniProtMesothelioma, malignant

UniProtVitreoretinopathy, exudative 7

627

ClinVar variants

158

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— CTNNB1

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Gene-Disease Validity (ClinGen)

CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

158 Pathogenic / Likely Pathogenic· 237 VUS of 627 total submissions

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Clinical Trials

12 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.

0.13LOEUF

pLI 1.000

Z-score 5.46

OE 0.03 (0.01–0.13)

Highly constrained

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

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.

3.85Z-score

OE missense 0.47 (0.42–0.53)

199 obs / 421.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

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.0.03 (0.01–0.13)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.42–0.53)

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.0.99

0≤1.21.6

LoF obs/exp: 1 / 36.7Missense obs/exp: 199 / 421.1Syn Z: 0.14

ClinVar Variant Classifications

627 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic113

Likely Pathogenic45

VUS237

Likely Benign201

Benign16

Conflicting15

113

Pathogenic

Likely Pathogenic

237

VUS

201

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	63	5	44	1	113
Likely Pathogenic	17	14	14	0	45
VUS	2	214	17	4	237
Likely Benign	0	4	94	103	201
Benign	0	0	13	3	16
Conflicting	—				15
Total	82	237	182	111	627

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

View in ClinVar →

Protein Context — Lollipop Plot

CTNNB1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CTNNB1-related exudative vitreoretinopathy

definitive

ADLoss Of FunctionAbsent Gene Product

Eye

G2P ↗

CTNNB1-related intellectual developmental disorder

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

CATENIN, BETA-1; CTNNB1

MIM #116806 · *

Colorectal cancer, somatic

MIM #114500