NM_015713.5:c.979C>T

Variant names:

• chr8-102208210-G-A
• rs121918310
• NM_015713.5:c.979C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_015713.5(RRM2B):​c.979C>T​(p.Arg327*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005400014: "In addition, functional studies using patient muscle cells were shown to have cytochrome C oxidase-deficient muscle fibres and mitochondrial DNA deletions (Tyynismaa, H., et al. (2009))."".

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRM2B NM_015713.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 3.66
• Publications: 5 publications found

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: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0729 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005400014: "In addition, functional studies using patient muscle cells were shown to have cytochrome C oxidase-deficient muscle fibres and mitochondrial DNA deletions (Tyynismaa, H., et al. (2009))."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-102208210-G-A is Pathogenic according to our data. Variant chr8-102208210-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015713.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	NM_015713.5	MANE Select	c.979C>T	p.Arg327*	stop_gained	Exon 9 of 9	NP_056528.2
	RRM2B	NM_001172477.1		c.1195C>T	p.Arg399*	stop_gained	Exon 9 of 9	NP_001165948.1	Q7LG56-6
	RRM2B	NM_001172478.2		c.823C>T	p.Arg275*	stop_gained	Exon 8 of 8	NP_001165949.1	Q7LG56-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	ENST00000251810.8	TSL:1 MANE Select	c.979C>T	p.Arg327*	stop_gained	Exon 9 of 9	ENSP00000251810.3	Q7LG56-1
	RRM2B	ENST00000395912.6	TSL:1	c.823C>T	p.Arg275*	stop_gained	Exon 8 of 8	ENSP00000379248.2	Q7LG56-2
	RRM2B	ENST00000519317.5	TSL:1	c.343C>T	p.Arg115*	stop_gained	Exon 4 of 4	ENSP00000430641.1	Q7LG56-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
3	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (4)
-	-	-	RRM2B-related mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.7
Vest4		0.69
ClinPred		1.0	D
GERP RS		2.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121918310; hg19: chr8-103220438; COSMIC: COSV52566674; COSMIC: COSV52566674;