TFAP2B

protein-coding

transcription factor AP-2 beta, the group of Transcription factor AP-2 family

Gene summary

This gene encodes a member of the AP-2 family of transcription factors. AP-2 proteins form homo- or hetero-dimers with other AP-2 family members and bind specific DNA sequences. They are thought to stimulate cell proliferation and suppress terminal differentiation of specific cell types during embryonic development. Specific AP-2 family members differ in their expression patterns and binding affinity for different promoters. This protein functions as both a transcriptional activator and repressor. Mutations in this gene result in autosomal dominant Char syndrome, suggesting that this gene functions in the differentiation of neural crest cell derivatives. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003221.4

Inheritance

ClinVar variants

P:28U:91B:36

Top phenotype

Char syndrome; Patent ductus arteriosus 2

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr6:50,818,723-50,847,619

External References & Databases

Ensembl (ENSG00000008196)

Transcript & Mutation Effects

hg38 • Region Span ~28.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial patent arterial ductSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018758

Submitter: Orphanet

patent ductus arteriosus 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014878

Submitter: PanelApp Australia

Char syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008209

Submitter: G2P

Char syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008209

Submitter: Labcorp Genetics (formerly Invitae)

TFAP2B-related congenital heart disease spectrum disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1010098

Submitter: ClinGen

*TFAP2B* is located on chromosome 6 at 6p12.3 and encodes the transcription factor AP-2β protein which is part of a family of AP-2 transcription factors, all of which play a role in development. Multiple disease entities have been reported in association with this gene: Char syndrome (MIM:169100), patent ductus arteriosus 2 (PDA) (MIM:617035), and syndromic craniosynostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in molecular mechanism and inheritance pattern between Char syndrome and PDA. Therefore, the following disease entities have been lumped into one disease entity: *TFAP2B*- related congenital heart disease spectrum disorder (MONDO:1010098). The syndromic craniosynostosis assertion has been split and will be curated when additional genetic evidence is published. *TFAP2B* was first reported in connection with autosomal dominant *TFAP2B*- related congenital heart disease spectrum disorder in 2000 (Satoda et al. 2000 PMID: 10802654). The disorder is characterized by PDA, facial dysmorphism (wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge and upturned nasal tip, short philtrum with a triangular mouth, and thickened, everted lips), hand anomalies (aplasia or hypoplasia of the middle phalanges of the fifth fingers). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twelve variants (7 missense, 3 splice site, 2 frameshift) reported in 12 probands in seven publications have been included in this curation (PMIDs: 10802654,15684060, 21643846,30579973,18752453, 11505339, 31012281). This gene-disease relationship is also supported by expression data, biochemical function studies, and two non-human model organisms (PMIDs: 21829553, 32878901, 8989526). In summary, there is definitive evidence supporting the relationship between *TFAP2B* and *TFAP2B*- related congenital heart disease spectrum disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 2nd, 2024 (SOP Version 11).

Char syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008209

Submitter: PanelApp Australia

Char syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008209

Submitter: Orphanet

Clinical Genomic Database (CGD)

Char syndrome; Patent ductus arteriosus 2AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 728571; 1342853; 8326495; 7645594; 9217229; 10368122; 10802654; 10955477; 11102923; 11505339; 15684060; 18752453; 21643846

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFAP2B variants in ClinVar

14 Conditions Cataloged

not providedTotal: 102

Inborn genetic diseasesTotal: 40

Char syndromeTotal: 26

Patent ductus arteriosus 2Total: 7

Craniosynostosis syndromeTotal: 4

TFAP2B-related disorderTotal: 4

not specifiedTotal: 4

Upslanted palpebral fissureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003221.4. 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			2 clinvar	28 clinvar	3 clinvar	33
missense	4 clinvar	6 clinvar	85 clinvar	4 clinvar	1 clinvar	100
nonsense	3 clinvar	5 clinvar				8
start loss		1 clinvar				1
frameshift	5 clinvar		2 clinvar			7
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	2 clinvar			6
Total	15	13	91	32	4	155

Highest pathogenic variant AF is 0.000001368122

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003221.4	RefSeq	NP_003212.2	7	MANE Select
ENST00000393655.4	Ensembl	ENSP00000377265.2	7	MANE Select
ENST00000344788.7	Ensembl	ENSP00000342252.3	4	Standard
ENST00001141519.1	Ensembl	ENSP00000811635.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neural Crest Differentiation
Preimplantation Embryo
Gene expression (Transcription)
Generic Transcription Pathway
SUMOylation of transcription factors

Biological Process

negative regulation of transcription by RNA polymerase II
kidney development
renal water homeostasis
glucose metabolic process
regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
enhancer sequence-specific DNA binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393655
Coding exons: 7
Length: 28891
Individuals with no LoFs: 125746
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125748
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.29	191	248	0.770	0.0000120	2959
Missense (PolyPhen)		25	58.322	0.42865		736
Synonymous	-0.812	123	112	1.10	0.00000580	966
Loss of Function	3.75	1	18.3	0.0546	8.16e-7	212

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
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: Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC. AP-2-beta appears to be required for normal face and limb development and for proper terminal differentiation and function of renal tubular epithelia. {ECO:0000269|PubMed:11694877}.;
Disease: DISEASE: Char syndrome (CHAR) [MIM:169100]: An autosomal dominant disorder characterized by patent ductus arteriosus (PDA), facial dysmorphism and hand anomalies. {ECO:0000269|PubMed:10802654, ECO:0000269|PubMed:11505339, ECO:0000269|PubMed:15684060}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Patent ductus arteriosus 2 (PDA2) [MIM:617035]: A congenital heart defect characterized by the persistent opening of fetal ductus arteriosus that fails to close after birth. Fetal ductus arteriosus connects the pulmonary artery to the descending aorta, allowing unoxygenated blood to bypass the lung and flow to the placenta. Normally, the ductus occludes shortly after birth. {ECO:0000269|PubMed:18752453, ECO:0000269|PubMed:21643846}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.247

Intolerance Scores

LoFtool: 0.0683
RVIS EVS: -0.32
RVIS percentile EVS: 31.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.969

Gene Damage Prediction

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