RAD21

protein-coding

RAD21 cohesin complex component, the group of Cohesin complex|Kleisins|MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006265.3

Inheritance

AD, AR

ClinVar variants

P:64U:208B:106

Top phenotype

Cornelia de Lange syndrome 4; Mungan syndrome

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr8:116,845,934-116,874,776

External References & Databases

Ensembl (ENSG00000164754)

Transcript & Mutation Effects

hg38 • Region Span ~28.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Mungan syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012657

Submitter: Labcorp Genetics (formerly Invitae)

Cornelia de Lange syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013864

Submitter: Labcorp Genetics (formerly Invitae)

Cornelia de Lange syndrome 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013864

Submitter: G2P

Cornelia de Lange syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013864

Submitter: PanelApp Australia

Cornelia de Lange syndrome 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013864

Submitter: Ambry Genetics

Cornelia de Lange syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016033

Submitter: ClinGen

RAD21 was reported in relation to autosomal dominant Cornelia de Lange syndrome (CdLS) as early as 2012 (Deardorff et al., PMID: 22633399). CdLS is characterized by phenotypes including intellectual disability, autism, developmental delay, characteristic facial dysmorphisms, short stature, and other skeletal anomalies. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven probands harboring missense and truncating variants as well as an in-frame deletion are documented here, although additional cases have been reported in the literature (PMIDs: 22633399, 24378232, 27882533, 27620904, 30716475, 30125677). While the majority of cases occurred de novo, variants in RAD21 segregated with CdLS-like features in 3 additional individuals in 1 family, although their phenotypes were considered too mild by the authors to be diagnosed with classical CdLS (PMID: 27882533). Of note, RAD21 has been associated with a milder form of CdLS compared to other genes such as NIPBL, HDAC8, and SMC1A. This gene-disease association is supported by animal models and a rescue experiment (PMIDs: 17567667, 25378554). In summary, RAD21 is definitively associated with autosomal dominant Cornelia de Lange syndrome.

Cornelia de Lange syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016033

Submitter: Orphanet

Mungan syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012657

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cornelia de Lange syndrome 4; Mungan syndromeAD/AR

Manifestation: Cardiovascular; Craniofacial; Dental; Gastrointestinal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular

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

Refs: 14638363; 17487221; 22633399; 25575569; 31334757

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAD21 variants in ClinVar

13 Conditions Cataloged

Cornelia de Lange syndrome 4Total: 287

not providedTotal: 170

Inborn genetic diseasesTotal: 95

not specifiedTotal: 50

RAD21-related disorderTotal: 30

Mungan syndromeTotal: 6

Intellectual disabilityTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006265.3. 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			4 clinvar	86 clinvar		90
missense	3 clinvar	10 clinvar	194 clinvar	19 clinvar		226
nonsense	10 clinvar	10 clinvar	1 clinvar			21
start loss	1 clinvar					1
frameshift	21 clinvar	2 clinvar	4 clinvar			27
splice donor/acceptor (+/-2bp)	4 clinvar	3 clinvar	5 clinvar	1 clinvar		13
Total	39	25	208	106	0	378

Highest pathogenic variant AF is 0.000013762309

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006265.3	RefSeq	NP_006256.1	13	MANE Select
ENST00000297338.7	Ensembl	ENSP00000297338.2	13	MANE Select
ENST00000517485.6	Ensembl	ENSP00000427923.2	13	Standard
ENST00000517485.7	Ensembl	ENSP00000427923.2	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rad21a	Danio rerio	Structure: nucleate erythrocyte Quality: increased accumulation abnormal

Gene / Model

Organism

Observed Phenotype

rad21a

Danio rerio

Structure: nucleate erythrocyte

Quality: increased accumulation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
Prion disease pathway
Regulation of sister chromatid separation at the metaphase-anaphase transition
Signal Transduction
SUMOylation of DNA damage response and repair proteins

Biological Process

double-strand break repair
DNA recombination
regulation of transcription by RNA polymerase II
apoptotic process
sister chromatid cohesion

Molecular Function

chromatin binding
protein binding

Cellular Component

chromosome, centromeric region
chromatin
condensed nuclear chromosome
nucleoplasm
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000297338
Coding exons: 13
Length: 28932
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125676
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.64	204	341	0.598	0.0000173	4208
Missense (PolyPhen)		27	95.321	0.28325		1159
Synonymous	-0.268	122	118	1.03	0.00000640	1117
Loss of Function	4.60	3	30.3	0.0990	0.00000141	397

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleavable component of the cohesin complex, involved in chromosome cohesion during cell cycle, in DNA repair, and in apoptosis. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At metaphase-anaphase transition, this protein is cleaved by separase/ESPL1 and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Also plays a role in apoptosis, via its cleavage by caspase-3/CASP3 or caspase-7/CASP7 during early steps of apoptosis: the C-terminal 64 kDa cleavage product may act as a nuclear signal to initiate cytoplasmic events involved in the apoptotic pathway. {ECO:0000269|PubMed:11875078, ECO:0000269|PubMed:12417729}.;
Disease: DISEASE: Cornelia de Lange syndrome 4 (CDLS4) [MIM:614701]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22633399}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.193

Intolerance Scores

LoFtool: 0.416
RVIS EVS: -0.51
RVIS percentile EVS: 21.41

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
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