MYCBP2

protein-coding

MYC binding protein 2, the group of Ring finger proteins

Gene summary

This gene encodes an E3 ubiquitin-protein ligase and member of the PHR (Phr1/MYCBP2, highwire and RPM-1) family of proteins. The encoded protein plays a role in axon guidance and synapse formation in the developing nervous system. In mammalian cells, this protein regulates the cAMP and mTOR signaling pathways, and may additionally regulate autophagy. Reduced expression of this gene has been observed in acute lymphoblastic leukemia patients and a mutation in this gene has been identified in patients with a rare inherited vision defect. [provided by RefSeq, Mar 2017]

MANE transcript

NM_015057.5

Inheritance

ClinVar variants

P:18U:747B:72

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr13:77,042,474-77,327,094

External References & Databases

Ensembl (ENSG00000005810)

Transcript & Mutation Effects

hg38 • Region Span ~284.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYCBP2 variants in ClinVar

14 Conditions Cataloged

Inborn genetic diseasesTotal: 450

not providedTotal: 306

MYCBP2-related disorderTotal: 101

See casesTotal: 2

MYCBP2-related developmental delay with corpus callosum defectsTotal: 2

not specifiedTotal: 2

MYCBP2-related neurodevelopmental conditionTotal: 1

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015057.5. 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		1 clinvar	9 clinvar	42 clinvar	7 clinvar	59
missense	3 clinvar	1 clinvar	688 clinvar	16 clinvar	6 clinvar	714
nonsense	5 clinvar	3 clinvar	13 clinvar			21
start loss			1 clinvar	1 clinvar		2
frameshift	1 clinvar	2 clinvar	13 clinvar			16
splice donor/acceptor (+/-2bp)		2 clinvar	23 clinvar			25
Total	9	9	747	59	13	837

Highest pathogenic variant AF is 0.0000018808495

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_015057.5	RefSeq	NP_055872.4	83	MANE Select
ENST00000544440.7	Ensembl	ENSP00000444596.2	83	MANE Select
ENST00000357337.11	Ensembl	ENSP00000349892.6	84	Standard
ENST00000357337.12	Ensembl	ENSP00000349892.6	84	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mycbp2	Danio rerio	Structure: retinal ganglion cell Quality: displaced abnormal

Gene / Model

Organism

Observed Phenotype

mycbp2

Danio rerio

Structure: retinal ganglion cell

Quality: displaced

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrated Breast Cancer Pathway

Biological Process

protein ubiquitination
branchiomotor neuron axon guidance
central nervous system projection neuron axonogenesis
regulation of protein localization
negative regulation of protein catabolic process

Molecular Function

guanyl-nucleotide exchange factor activity
protein binding
zinc ion binding
Ran GTPase binding
protein homodimerization activity

Cellular Component

nucleus
cytoplasm
microtubule cytoskeleton
membrane
axon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000544440
Coding exons: 83
Length: 282394
Individuals with no LoFs: 125710
Homozygous LoFs: 0
Heterozygous LoFs: 38
Defined: 125748
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	6.05	1566	2.40e+3	0.653	0.000122	30359
Missense (PolyPhen)		702	1343.9	0.52237		17269
Synonymous	0.0144	848	849	0.999	0.0000443	8938
Loss of Function	13.0	18	233	0.0773	0.0000130	2916

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues (PubMed:29643511). Shows esterification activity towards both threonine and serine, with a preference for threonine, and acts via two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates (PubMed:29643511). Interacts with the E2 enzymes UBE2D1, UBE2D3, UBE2E1 and UBE2L3 (PubMed:18308511, PubMed:29643511). Plays a key role in neural development, probably by mediating ubiquitination of threonine residues on target proteins (Probable). Involved in different processes such as regulation of neurite outgrowth, synaptic growth, synaptogenesis and axon degeneration (By similarity). Required for the formation of major central nervous system axon tracts (By similarity). Required for proper axon growth by regulating axon navigation and axon branching: acts by regulating the subcellular location and stability of MAP3K12/DLK (By similarity). Required for proper localization of retinogeniculate projections but not for eye-specific segregation (By similarity). Regulates axon guidance in the olfactory system (By similarity). Involved in Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons: acts by promoting destabilization of NMNAT2, probably via ubiquitination of NMNAT2 (By similarity). Catalyzes ubiquitination of threonine and/or serine residues on NMNAT2, consequences of threonine and/or serine ubiquitination are however unknown (PubMed:29643511). Regulates the internalization of TRPV1 in peripheral sensory neurons (By similarity). May mediate ubiquitination and subsequent proteasomal degradation of TSC2/tuberin (PubMed:18308511). Independently of the E3 ubiquitin-protein ligase activity, also acts as a guanosine exchange factor (GEF) for RAN in neurons of dorsal root ganglia (PubMed:26304119). May function as a facilitator or regulator of transcriptional activation by MYC (PubMed:9689053). {ECO:0000250|UniProtKB:Q7TPH6, ECO:0000269|PubMed:18308511, ECO:0000269|PubMed:26304119, ECO:0000269|PubMed:29643511, ECO:0000269|PubMed:9689053}.;

Recessive Scores

pRec: 0.110

Essentials

Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.930

Gene Damage Prediction

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