rs515726201

Positions:

• chr8-102208223-A-AT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000251810.8(RRM2B):​c.965_966insA​(p.Asn322LysfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRM2B ENST00000251810.8 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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 0.0862 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-102208223-A-AT is Pathogenic according to our data. Variant chr8-102208223-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 30433.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRM2B	NM_015713.5	c.965_966insA	p.Asn322LysfsTer4	frameshift_variant	9/9	ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1	c.1181_1182insA	p.Asn394LysfsTer4	frameshift_variant	9/9		NP_001165948.1
RRM2B	NM_001172478.2	c.809_810insA	p.Asn270LysfsTer4	frameshift_variant	8/8		NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8	c.965_966insA	p.Asn322LysfsTer4	frameshift_variant	9/9	1	NM_015713.5	ENSP00000251810	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 07, 2011

- -

RRM2B-related mitochondrial disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs515726201; hg19: chr8-103220451;