CREBBP

protein-coding

CREB binding protein, the group of Bromodomain containing|Lysine acetyltransferases|Zinc fingers ZZ-type

Gene summary

This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein p300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

Previous symbols:

RSTS

MANE transcript

NM_004380.3

Inheritance

ClinVar variants

P:540U:1344B:1086

Top phenotype

Rubinstein-Taybi syndrome; Menke-Hennekam syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr16:3,725,054-3,880,713

External References & Databases

Ensembl (ENSG00000005339)

Transcript & Mutation Effects

hg38 • Region Span ~155.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Rubinstein-Taybi syndrome due to CREBBP mutationsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008393

Submitter: Ambry Genetics

Rubinstein-Taybi syndrome due to CREBBP mutationsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008393

Submitter: G2P

Menke-Hennekam syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020763

Submitter: G2P

Rubinstein-Taybi syndrome due to CREBBP mutationsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008393

Submitter: Labcorp Genetics (formerly Invitae)

Rubinstein-Taybi syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019188

Submitter: Illumina

Rubinstein-Taybi syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019188

Submitter: ClinGen

*CREBBP* was first reported in relation to autosomal dominant Rubinstein-Taybi syndrome in 1995 (Petrij et al., PMID: 7630403). *CREBBP* encodes a transcriptional coactivator with histone acetyltransferase activity. Rubinstein-Taybi syndrome is characterized by intellectual disability, distinctive facial dysmorphisms, broad digits, short stature, and microcephaly. Eight variants (nonsense, frameshift, missense, splice site, and deletion) that have been reported in eight probands in four publications (PMIDs: 11331617, 12070251, 12566391, 18792986) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including a *Crebbp*-deficient mouse model, a rescue experiment, and biochemical function (PMIDs: 9294190, 11331617, 12566391, 12930888). In summary, there is definitive evidence supporting the relationship between *CREBBP* and autosomal dominant Rubinstein-Taybi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2018 (SOP Version 5). As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.

Menke-Hennekam syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020763

Submitter: Ambry Genetics

Menke-Hennekam syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020763

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Rubinstein-Taybi syndrome; Menke-Hennekam syndrome 1AD

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic ; Oncologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Hematologic; Cardiovascular; Oncologic; Ophthalmologic

Rationale: Rubinstein-Taybi syndrome can include a risk of frequent infections (especially respiratory infections), and prophylaxis and early and aggressive treatment of infections may be beneficial; There may be increased risk of malignancy, and awareness may allow early detection and treatment of oncologic processes; Due to the possibility of cardiovascular anomalies (including arrhythmia), surveillance may be beneficial; Surveillance for certain types of ophthalmologic manifestations (eg, glaucoma) may be beneficial in order to allow prompt treatment; Menke-Hennekam syndrome can include frequent infections, and prophylaxis and early and aggressive treatment of infections may be beneficial; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 13983033; 7137629; 7747773; 7630403; 10573006; 15706485; 16913274; 18792986; 19852432; 20301699; 20717166; 20949605; 21085895; 21189944; 22426292; 23432975; 27311832; 29460469; 30737887

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CREBBP variants in ClinVar

44 Conditions Cataloged

Rubinstein-Taybi syndromeTotal: 1588

CREBBP-related disorderTotal: 1124

not providedTotal: 955

Rubinstein-Taybi syndrome due to CREBBP mutationsTotal: 703

Inborn genetic diseasesTotal: 462

not specifiedTotal: 399

Menke-Hennekam syndrome 1Total: 344

Intellectual disabilityTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004380.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			28 clinvar	669 clinvar	64 clinvar	761
missense	26 clinvar	114 clinvar	1263 clinvar	322 clinvar	29 clinvar	1754
nonsense	97 clinvar	22 clinvar	14 clinvar			133
start loss	3 clinvar					3
frameshift	165 clinvar	50 clinvar	17 clinvar	2 clinvar		234
splice donor/acceptor (+/-2bp)	39 clinvar	24 clinvar	22 clinvar			85
Total	330	210	1344	993	93	2970

Highest pathogenic variant AF is 0.000019466046

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004380.3	RefSeq	NP_004371.2	31	MANE Select
ENST00000262367.10	Ensembl	ENSP00000262367.5	31	MANE Select
NM_001079846.1	RefSeq	NP_001073315.1	30	Standard
ENST00000382070.7	Ensembl	ENSP00000371502.3	30	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Renal cell carcinoma - Homo sapiens (human)
Long-term potentiation - Homo sapiens (human)
Adherens junction - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
response to hypoxia
stimulatory C-type lectin receptor signaling pathway
regulation of transcription, DNA-templated
transcription initiation from RNA polymerase II promoter

Molecular Function

proximal promoter sequence-specific DNA binding
RNA polymerase II transcription factor binding
RNA polymerase II activating transcription factor binding
p53 binding
chromatin binding

Cellular Component

histone acetyltransferase complex
nuclear chromatin
nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262367
Coding exons: 31
Length: 155673
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.90	1005	1.42e+3	0.709	0.0000896	15988
Missense (PolyPhen)		127	226.43	0.56089		2771
Synonymous	-4.84	714	567	1.26	0.0000401	4824
Loss of Function	9.83	3	118	0.0253	0.00000679	1208

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0027	0.0014	notable
Latino/Admixed American	0.00023	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK- ARNTL/BMAL1 heterodimers. Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493). {ECO:0000269|PubMed:11154691, ECO:0000269|PubMed:12738767, ECO:0000269|PubMed:12929931, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:24939902, ECO:0000269|PubMed:25514493, ECO:0000269|PubMed:9707565}.;
Disease: DISEASE: Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription.; DISEASE: Rubinstein-Taybi syndrome 1 (RSTS1) [MIM:180849]: A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. {ECO:0000269|PubMed:11331617, ECO:0000269|PubMed:12114483, ECO:0000269|PubMed:12566391, ECO:0000269|PubMed:15706485, ECO:0000269|PubMed:20684013, ECO:0000269|PubMed:24616510, ECO:0000269|PubMed:25388907}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=De novo missense mutations in the last part of exon 30 or beginning of exon 31 are associated with growth retardation, craniofacial dysmorphism and additional Rubinstein-Taybi-like features. No patients have broad thumbs. Patients have intellectual disability of variable severity, a marked speech delay, short stature and microcephaly. Main facial characteristics include short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella and long philtrum. {ECO:0000269|PubMed:27311832}.;

Recessive Scores

pRec: 0.551

Intolerance Scores

LoFtool: 0.00110
RVIS EVS: -2.1
RVIS percentile EVS: 1.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium