TP53BP2

protein-coding

tumor protein p53 binding protein 2, the group of Protein phosphatase 1 regulatory subunits|Ankyrin repeat domain containing

Gene summary

This gene encodes a member of the ASPP (apoptosis-stimulating protein of p53) family of p53 interacting proteins. The protein contains four ankyrin repeats and an SH3 domain involved in protein-protein interactions. It is localized to the perinuclear region of the cytoplasm, and regulates apoptosis and cell growth through interactions with other regulatory molecules including members of the p53 family. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001031685.3

Inheritance

ClinVar variants

U:150B:25

Top phenotype

TP53BP2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr1:223,779,893-223,845,954

External References & Databases

Ensembl (ENSG00000143514)

Transcript & Mutation Effects

hg38 • Region Span ~66.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tourette syndromeNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

open-angle glaucomaNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005338

Submitter: ClinGen

*TP53BP2* was first reported in relation to autosomal dominant primary open angle glaucoma in 2018 (Michale, et al., PMID: 28150229). Primary open angle glaucoma is characterized by a loss of retinal ganglion cells, visual field defects, and cupping of the optic disc. This curation includes one missense variant reported in one proband in one publication (PMID: 28150229). This proband was also reported to have a variant in the *MAPKAPK2* gene, and group members were therefore unable to conclusively confirm the cause of the phenotype within this proband. This gene-disease association is not supported by any experimental evidence. The *TP53BP2* gene is expressed in the human cornea (PMID: 11709013), and its gene product reportedly interacts with components of apoptosis pathways and may regulate cell cycle progression (PMID: 8668206), but the relevance of this evidence to primary open-angle glaucoma is not yet clear. In summary, the gene-disease relationship between *TP53BP2* and primary open angle glaucoma is classified as disputed. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on May 18th, 2023.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TP53BP2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 138

TP53BP2-related disorderTotal: 18

not providedTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001031685.3. 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			2 clinvar	6 clinvar	8 clinvar	16
missense			143 clinvar	8 clinvar	3 clinvar	154
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	150	14	11	175

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001031685.3	RefSeq	NP_001026855.2	18	MANE Select
ENST00000343537.12	Ensembl	ENSP00000341957.7	18	MANE Select
NM_005426.3	RefSeq	NP_005417.1	14	Standard
ENST00000391878.6	Ensembl	ENSP00000375750.2	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tp53bp2b	Danio rerio	Structure: otolith Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

tp53bp2b

Danio rerio

Structure: otolith

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hippo signaling pathway - Homo sapiens (human)
Gene expression (Transcription)
Generic Transcription Pathway
TP53 Regulates Transcription of Cell Death Genes
RNA Polymerase II Transcription

Biological Process

cell cycle
signal transduction
regulation of apoptotic process
negative regulation of cell cycle
intrinsic apoptotic signaling pathway by p53 class mediator

Molecular Function

p53 binding
SH3/SH2 adaptor activity
protein binding
SH3 domain binding
identical protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343537
Coding exons: 18
Length: 66074
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.89	498	632	0.788	0.0000356	7420
Missense (PolyPhen)		188	283.29	0.66364		3220
Synonymous	0.400	226	234	0.967	0.0000138	2186
Loss of Function	4.96	16	56.1	0.285	0.00000292	647

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0.00012	0.000099	rare
East Asian	0.00017	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00020	0.00020	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulator that plays a central role in regulation of apoptosis and cell growth via its interactions. Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo. Inhibits the ability of APPBP1 to conjugate NEDD8 to CUL1, and thereby decreases APPBP1 ability to induce apoptosis. Impedes cell cycle progression at G2/M. Its apoptosis-stimulating activity is inhibited by its interaction with DDX42. {ECO:0000269|PubMed:11684014, ECO:0000269|PubMed:12694406, ECO:0000269|PubMed:19377511}.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.758
RVIS EVS: -1.13
RVIS percentile EVS: 6.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.816

Gene Damage Prediction

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