8-102239027-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 361183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	NM_015713.5	MANE Select	c.-153G>T		upstream_gene	N/A	NP_056528.2
	RRM2B	NM_001172477.1		c.-205G>T		upstream_gene	N/A	NP_001165948.1
	RRM2B	NM_001172478.2		c.-153G>T		upstream_gene	N/A	NP_001165949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	ENST00000251810.8	TSL:1 MANE Select	c.-153G>T		upstream_gene	N/A	ENSP00000251810.3
	RRM2B	ENST00000395912.6	TSL:1	c.-153G>T		upstream_gene	N/A	ENSP00000379248.2
	RRM2B	ENST00000519317.5	TSL:1	c.-153G>T		upstream_gene	N/A	ENSP00000430641.1

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

African (AFR) AF: 0.00459 AC: 77 AN: 16758

American (AMR) AF: 0.104 AC: 3381 AN: 32624

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 488 AN: 18314

East Asian (EAS) AF: 0.357 AC: 11432 AN: 31980

South Asian (SAS) AF: 0.0768 AC: 4628 AN: 60282

European-Finnish (FIN) AF: 0.0296 AC: 944 AN: 31860

Middle Eastern (MID) AF: 0.0165 AC: 44 AN: 2660

European-Non Finnish (NFE) AF: 0.0113 AC: 4318 AN: 383232

Other (OTH) AF: 0.0461 AC: 1466 AN: 31776

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

African (AFR) AF: 0.00485 AC: 200 AN: 41260

American (AMR) AF: 0.0825 AC: 1255 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3462

East Asian (EAS) AF: 0.383 AC: 1905 AN: 4972

South Asian (SAS) AF: 0.0877 AC: 417 AN: 4756

European-Finnish (FIN) AF: 0.0290 AC: 304 AN: 10486

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.0115 AC: 776 AN: 67646

Other (OTH) AF: 0.0495 AC: 104 AN: 2100

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		-0.31
PromoterAI		-0.039	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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