chr8-102218827-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_015713.5(RRM2B):c.671T>G(p.Ile224Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

RRM2B
NM_015713.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:2

Conservation

PhyloP100: 9.26

Publications

8 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: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015713.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 8-102218827-A-C is Pathogenic according to our data. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102218827-A-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2B	NM_015713.5 link	c.671T>G	p.Ile224Ser	missense_variant	Exon 6 of 9	ENST00000251810.8	NP_056528.2	Q7LG56-1
RRM2B	NM_001172477.1 link	c.887T>G	p.Ile296Ser	missense_variant	Exon 6 of 9		NP_001165948.1	Q7LG56-6
RRM2B	NM_001172478.2 link	c.515T>G	p.Ile172Ser	missense_variant	Exon 5 of 8		NP_001165949.1	Q7LG56-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8 link	c.671T>G	p.Ile224Ser	missense_variant	Exon 6 of 9	1	NM_015713.5	ENSP00000251810.3		Q7LG56-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152056

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251124

AF XY:

0.00000737

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460400

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1110670

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000263

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000173

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RRM2B-related mitochondrial disease

Pathogenic:1Other:2

Mar 15, 2023

Clinical Genomic Analysis (GENYSIS) Core, University of North Carolina at Chapel Hill

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

RRM2B c.671T>G, p.(Ile224Ser), is a missense variant that changes a single amino acid from a highly conserved isoleucine to a serine. This is a rare variant present at an allele frequency of 0.0026% (4/152,056 alleles) in the gnomADv3.1 population database and reported as pathogenic/likely pathogenic by several clinical laboratories in the ClinVar database. In addition, multiple in silico models predict that the variant has a damaging effect on the protein. The RRM2B c.671T>G variant has previously been reported in an individual with late-onset PEO at 48 years, proximal muscle weakness, cataracts, and migraine (PMID: 23107649). The variant has also been reported as homozygous or in trans with another pathogenic variant in at least two individuals with neonatal-onset autosomal recessive MDMDs (PMID: 18504129, PMID: 30049826). Based on the available information, we consider this variant likely pathogenic. ACMG codes: PM2_Supporting (rare in gnomAD), PM3 (detected in trans with a pathogenic variant), PP3_Strong (REVEL score >= 0.932). -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 05-12-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Pathogenic:2

Dec 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 224 of the RRM2B protein (p.Ile224Ser). This variant is present in population databases (rs515726196, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions and autosomal recessive mitochondrial DNA depletion syndrome (PMID: 18504129, 23107649, 31462754; Invitae). ClinVar contains an entry for this variant (Variation ID: 132122). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RRM2B protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 27, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30049826, 24741716, 18504129, 23107649) -

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

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 8a

Pathogenic:1

Mar 16, 2018

Centre for Translational Omics - GOSgene, University College London

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

Pathogenic:1

Feb 10, 2025

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The highest population allele frequency in gnomAD v4.0 is 0.00003127 (0.003%; 2/63966 alleles in the European/Finnish population). PP3_Strong: Revel score is 0.987. PP1 Not Met: 1 informative meiosis in 1 family (clinical testing). PS4_Moderate: 5 unrelated probands with consistent phenotype for disorder (PMID:23107649, PMID:24086434). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.7

D;.;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.98

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

5.4

Varity_R

0.97

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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