rs515726184

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4_SupportingPP5

The NM_015713.5(RRM2B):c.253_255delGAG(p.Glu85del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RRM2B
NM_015713.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 7.97

Publications

2 publications found

Variant links:

Genes affected

RRM2B (HGNC:17296): (ribonucleotide reductase regulatory TP53 inducible subunit M2B) This gene encodes the small subunit of a p53-inducible ribonucleotide reductase. This heterotetrameric enzyme catalyzes the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The product of this reaction is necessary for DNA synthesis. Mutations in this gene have been associated with autosomal recessive mitochondrial DNA depletion syndrome, autosomal dominant progressive external ophthalmoplegia-5, and mitochondrial neurogastrointestinal encephalopathy. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

RRM2B Gene-Disease associations (from GenCC):

mitochondrial DNA depletion syndrome 8a
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant progressive external ophthalmoplegia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kearns-Sayre syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial neurogastrointestinal encephalomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RRM2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_015713.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 8-102225983-TCTC-T is Pathogenic according to our data. Variant chr8-102225983-TCTC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132109.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RRM2B	NM_015713.5 link	c.253_255delGAG	p.Glu85del	conservative_inframe_deletion	Exon 3 of 9	ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1 link	c.469_471delGAG	p.Glu157del	conservative_inframe_deletion	Exon 3 of 9		NP_001165948.1
RRM2B	NM_001172478.2 link	c.97_99delGAG	p.Glu33del	conservative_inframe_deletion	Exon 2 of 8		NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8 link	c.253_255delGAG	p.Glu85del	conservative_inframe_deletion	Exon 3 of 9	1	NM_015713.5	ENSP00000251810.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251302

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460530

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

726636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1110920

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.253_255del, results in the deletion of 1 amino acid(s) of the RRM2B protein (p.Glu85del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs515726184, gnomAD 0.002%). This variant has been observed in individuals with clinical features of autosomal dominant progressive external ophthalmoplegia (PMID: 21378381, 31521625; Invitae). This variant has been reported in individual(s) with autosomal recessive mitochondrial DNA depletion syndrome (PMID: 17486094); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 132109). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Aug 25, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in the heterozygous state in two adults with late-onset progressive external ophthalmoplegia (PMID: 21378381, 31521625); Reported previously in trans with a missense variant in an infant with severe mitochondrial depletion (PMID: 17486094); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 31521625, 29241262, 33300680, 21378381, 24741716, 17486094)

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction;C2749861:Mitochondrial DNA depletion syndrome 8a;C2751319:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

Pathogenic:1

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Idiopathic camptocormia

Pathogenic:1

Jan 01, 2013

Department of Neurology, University Hospital of Strasbourg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mitochondrial DNA depletion syndrome 8a

Pathogenic:1

Jun 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction

Pathogenic:1

Sep 29, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: In-frame deletion in a non-repetitive region that has high conservation; Variant is present in gnomAD <0.01 (v4: 25 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified twice as likely pathogenic and once as a VUS by clinical laboratories in ClinVar. It has been reported multiple times in heterozygous individuals with late-onset progressive external ophthalmoplegia and mitochondrial-related myopathy (PMIDs: 21378381, 26969127, 39533303), and once in an assumed compound heterozygous neonate with mitochondrial depletion syndrome (PMID: 17486094). - This variant has moderate functional evidence supporting abnormal protein function. Protein blot analysis showed p53R2 protein was barely detectable in a muscle sample of an affected individual with this variant and p.(Cys236Phe) (PMID: 17486094). Additional information: This variant is heterozygous; This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance has been reported in the context of mitochondrial depletion syndrome type 8A/8B (MIM#612075) and rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (MIM#268315). Autosomal dominant inheritance has been reported for progressive external ophthalmoplegia with mitochondrial DNA deletions 5 (MIM#613077) (PMIDs: 23107649, 31462754); No published segregation evidence has been identified for this variant; No comparable in-frame deletion variants have previous evidence for pathogenicity; Variant is located in the annotated ribonucleotide reductase, small chain domain (DECIPHER); Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 5 (MIM#613077), autosomal recessive mitochondrial DNA depletion syndrome type 8A/8B (MIM#612075) and rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (MIM#268315). Missense variants have been reported as having either a loss of function or dominant negative effect (PMID: 23107649); This variant has been shown to be paternally inherited by trio analysis.

RRM2B-related mitochondrial disease

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over