CBX2

protein-coding

chromobox 2, the group of Chromobox family

Gene summary

This gene encodes a component of the polycomb multiprotein complex, which is required to maintain the transcriptionally repressive state of many genes throughout development via chromatin remodeling and modification of histones. Disruption of this gene in mice results in male-to-female gonadal sex reversal. Mutations in this gene are also associated with gonadal dysgenesis in humans. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2010]

Previous symbols:

CDCA6

MANE transcript

NM_005189.3

Inheritance

AR, SD, AD

ClinVar variants

P:2U:126B:51

Top phenotype

46,XY sex reversal 5

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:79,778,148-79,787,983

External References & Databases

Ensembl (ENSG00000173894)

Transcript & Mutation Effects

hg38 • Region Span ~9.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

46,XY sex reversal 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013120

Submitter: Labcorp Genetics (formerly Invitae)

46,XY sex reversal 5LIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0013120

Submitter: Ambry Genetics

46,XY complete gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010765

Submitter: Orphanet

Clinical Genomic Database (CGD)

46,XY sex reversal 5AR

Manifestation: Endocrine; Genitourinary

Intervention: General

Rationale: There was no evidence for dysgenetic gonads in the reported patient; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19361780

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CBX2 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 103

not providedTotal: 91

CBX2-related disorderTotal: 17

46,XY sex reversal 5Total: 6

Disorder of sexual differentiationTotal: 2

Pure gonadal dysgenesis 46,XYTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005189.3. 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			1 clinvar	31 clinvar	5 clinvar	37
missense	2 clinvar		123 clinvar	12 clinvar	3 clinvar	140
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	0	126	43	8	179

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005189.3	RefSeq	NP_005180.1	5	MANE Select
ENST00000310942.9	Ensembl	ENSP00000308750.4	5	MANE Select
NM_032647.4	RefSeq	NP_116036.1	4	Standard
ENST00000269399.5	Ensembl	ENSP00000269399.5	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Gene expression (Transcription)
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
Generic Transcription Pathway
Oxidative Stress Induced Senescence

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin organization
cell differentiation
development of primary sexual characteristics

Molecular Function

DNA binding
chromatin binding
protein binding
methylated histone binding

Cellular Component

euchromatin
heterochromatin
nucleus
nucleoplasm
PcG protein complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310942
Coding exons: 5
Length: 9852
Individuals with no LoFs: 123467
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 123471
p: 0.0000162

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.262	345	332	1.04	0.0000209	3407
Missense (PolyPhen)		95	104.49	0.90916		1133
Synonymous	-2.98	196	150	1.31	0.0000103	1135
Loss of Function	3.67	0	15.7	0.00	8.58e-7	190

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000020	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a Polycomb group (PcG) multiprotein PRC1- like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:21282530). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:21282530). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) or at 'Lys-27' (H3K27me3) (By similarity). Plays a role in the lineage differentiation of the germ layers in embryonic development (By similarity). Involved in sexual development, acting as activator of NR5A1 expression (PubMed:19361780). {ECO:0000250|UniProtKB:P30658, ECO:0000269|PubMed:19361780, ECO:0000269|PubMed:21282530}.;
Disease: DISEASE: 46,XY sex reversal 5 (SRXY5) [MIM:613080]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:19361780}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.0658
RVIS EVS: -0.66
RVIS percentile EVS: 16.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

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