rs2290707

Variant names:

• chr8-102239027-C-A
• rs2290707
• NM_015713.5:c.-153G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015713.5(RRM2B):​c.-153G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 760,574 control chromosomes in the GnomAD database, including 3,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (522 hom., cov: 31)
  • Exomes 𝑓: 0.044 (2757 hom.)
• Consequence: RRM2B NM_015713.5 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.308

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 8-102239027-C-A is Benign according to our data. Variant chr8-102239027-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 361183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-102239027-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2B	NM_015713.5	c.-153G>T		upstream_gene_variant		ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1	c.-205G>T		upstream_gene_variant			NP_001165948.1
RRM2B	NM_001172478.2	c.-153G>T		upstream_gene_variant			NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8	c.-153G>T		upstream_gene_variant		1	NM_015713.5	ENSP00000251810.3

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5034 AN: 150976 Hom.: 513 Cov.: 31

Gnomad AFR AF: 0.00486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0419

GnomAD4 exome AF: 0.0439 AC: 26778 AN: 609486 Hom.: 2757 Cov.: 8 AF XY: 0.0447 AC XY: 14391 AN XY: 321844

Gnomad4 AFR exome AF: 0.00459

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.0768

Gnomad4 FIN exome AF: 0.0296

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0461

GnomAD4 genome AF: 0.0335 AC: 5058 AN: 151088 Hom.: 522 Cov.: 31 AF XY: 0.0375 AC XY: 2766 AN XY: 73788

Gnomad4 AFR AF: 0.00485

Gnomad4 AMR AF: 0.0825

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.0877

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0495

Alfa AF: 0.0209 Hom.: 15

Bravo AF: 0.0375

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial DNA depletion syndrome 8a Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.4
DANN	Benign	0.81

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: rs2290707; hg19: chr8-103251255; COSMIC: COSV52567929; COSMIC: COSV52567929;