RRM2B

ribonucleotide reductase regulatory TP53 inducible subunit M2B

Basic information

Region (hg38): 8:102204502-102238961

Links

ENSG00000048392 ∙ NCBI:50484 ∙ OMIM:604712 ∙ HGNC:17296 ∙ Uniprot:Q7LG56 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial DNA depletion syndrome 8a (Strong), mode of inheritance: AR
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (Strong), mode of inheritance: AD
• Kearns-Sayre syndrome (Supportive), mode of inheritance: AR
• mitochondrial neurogastrointestinal encephalomyopathy (Supportive), mode of inheritance: AR
• autosomal dominant progressive external ophthalmoplegia (Supportive), mode of inheritance: AD
• mitochondrial DNA depletion syndrome 8a (Supportive), mode of inheritance: AR
• adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy (Supportive), mode of inheritance: AD
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (Strong), mode of inheritance: AD
• mitochondrial DNA depletion syndrome 8a (Strong), mode of inheritance: AR
• mitochondrial DNA depletion syndrome 8a (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction; Mitochondrial DNA depletion syndrome 8A	AR	Audiologic/Otolaryngologic; Renal	In Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The conditions can include renal impairment, and early awareness may enable medical management	Audiologic/Otolaryngologic; Biochemical; Gastrointestinal; Musculoskeletal; Neurologic; Renal	17486094; 19667227; 19138848; 19664747; 30439532; 32827185

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RRM2B gene.

• not_provided (272 variants)
• Mitochondrial_DNA_depletion_syndrome_8a (80 variants)
• Progressive_external_ophthalmoplegia_with_mitochondrial_DNA_deletions,_autosomal_dominant_5 (57 variants)
• Rod-cone_dystrophy,_sensorineural_deafness,_and_Fanconi-type_renal_dysfunction (46 variants)
• RRM2B-related_mitochondrial_disease (34 variants)
• Inborn_genetic_diseases (19 variants)
• not_specified (19 variants)
• RRM2B-related_disorder (17 variants)
• Progressive_external_ophthalmoplegia (3 variants)
• Mitochondrial_DNA_depletion_syndrome_8B_(MNGIE_type) (2 variants)
• Mitochondrial_disease (2 variants)
• Severe_lactic_acidosis (1 variants)
• Rod-cone_dystrophy (1 variants)
• Adult_Fanconi_syndrome (1 variants)
• Sensorineural_hearing_loss_disorder (1 variants)
• Idiopathic_camptocormia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RRM2B gene is commonly pathogenic or not. These statistics are base on transcript: NM_000015713.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	3	51		55
missense	4	19	126	3		152
nonsense	4	5	2			11
start loss		1				1
frameshift	6	5	3			14
splice donor/acceptor (+/-2bp)	3	7	4			14
Total	17	38	138	54	0

Highest pathogenic variant AF is 0.00005147804

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RRM2B	protein_coding	protein_coding	ENST00000251810	9	34617

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125734	0	13	125747	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.21	137	183	0.749	0.00000910	2337
Missense in Polyphen		32	60.374	0.53003		856
Synonymous	0.839	51	59.2	0.861	0.00000290	616
Loss of Function	2.58	8	20.7	0.387	0.00000106	251

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000968	0.0000967
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free radical center required for catalysis. Forms an active ribonucleotide reductase (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage. {ECO:0000269|PubMed:10716435, ECO:0000269|PubMed:11517226, ECO:0000269|PubMed:11719458}.
• Disease: DISEASE: Mitochondrial DNA depletion syndrome 8A (MTDPS8A) [MIM:612075]: A disorder due to mitochondrial dysfunction characterized by various combinations of neonatal hypotonia, neurological deterioration, respiratory distress, lactic acidosis, and renal tubulopathy. {ECO:0000269|PubMed:17486094, ECO:0000269|PubMed:18504129}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial DNA depletion syndrome 8B (MTDPS8B) [MIM:612075]: A disease due to mitochondrial dysfunction and characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy. {ECO:0000269|PubMed:19667227}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 5 (PEOA5) [MIM:613077]: A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. {ECO:0000269|PubMed:19664747}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Pyrimidine metabolism - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);Glutathione metabolism - Homo sapiens (human);Drug metabolism - other enzymes - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Gemcitabine Pathway, Pharmacodynamics;Pyrimidine Metabolism;UMP Synthase Deiciency (Orotic Aciduria);Gemcitabine Action Pathway;MNGIE (Mitochondrial Neurogastrointestinal Encephalopathy);Gemcitabine Metabolism Pathway;Beta Ureidopropionase Deficiency;Dihydropyrimidinase Deficiency;miRNA Regulation of DNA Damage Response;TP53 Regulates Metabolic Genes;Pyrimidine metabolism;Nucleotide Metabolism;DNA Damage Response;pyrimidine deoxyribonucleotides <i>de novo</i> biosynthesis;Gene expression (Transcription);Generic Transcription Pathway;Metabolism of nucleotides;Interconversion of nucleotide di- and triphosphates;RNA Polymerase II Transcription;Purine metabolism;Metabolism;Pyrimidine metabolism;TP53 Regulates Metabolic Genes;superpathway of purine nucleotide salvage;Transcriptional Regulation by TP53;superpathway of pyrimidine deoxyribonucleotides <i>de novo</i> biosynthesis;pyrimidine deoxyribonucleotides biosynthesis from CTP;Direct p53 effectors;guanosine deoxyribonucleotides <i>de novo</i> biosynthesis;guanosine nucleotides <i>de novo</i> biosynthesis;adenosine deoxyribonucleotides <i>de novo</i> biosynthesis;purine nucleotides <i>de novo</i> biosynthesis (Consensus)

Recessive Scores

• pRec: 0.205

Intolerance Scores

• loftool: 0.147
• rvis_EVS: -0.08
• rvis_percentile_EVS: 47.79

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.957

Gene ontology

• Biological process: kidney development;renal system process;mitochondrial DNA replication;DNA repair;response to oxidative stress;deoxyribonucleoside triphosphate metabolic process;deoxyribonucleotide biosynthetic process;response to amine;oxidation-reduction process;negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator
• Cellular component: nucleoplasm;mitochondrion;cytosol
• Molecular function: ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor;protein binding;metal ion binding