8-102214854-G-A

Variant names:

• chr8-102214854-G-A
• rs2853228
• NM_015713.5:c.685-696C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015713.5(RRM2B):​c.685-696C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 150,108 control chromosomes in the GnomAD database, including 63,908 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.92 (63908 hom., cov: 26)
• Consequence: RRM2B NM_015713.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.803
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2B	NM_015713.5	c.685-696C>T		intron_variant	Intron 6 of 8	ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1	c.901-696C>T		intron_variant	Intron 6 of 8		NP_001165948.1
RRM2B	NM_001172478.2	c.529-696C>T		intron_variant	Intron 5 of 7		NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8	c.685-696C>T		intron_variant	Intron 6 of 8	1	NM_015713.5	ENSP00000251810.3

Frequencies

GnomAD3 genomes AF: 0.918 AC: 137762 AN: 150002 Hom.: 63848 Cov.: 26

Gnomad AFR AF: 0.983

Gnomad AMI AF: 0.919

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.914

Gnomad NFE AF: 0.921

Gnomad OTH AF: 0.916

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.918 AC: 137874 AN: 150108 Hom.: 63908 Cov.: 26 AF XY: 0.913 AC XY: 66898 AN XY: 73300

African (AFR) AF: 0.983 AC: 40590 AN: 41298

American (AMR) AF: 0.924 AC: 13991 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3161 AN: 3462

East Asian (EAS) AF: 0.534 AC: 2741 AN: 5130

South Asian (SAS) AF: 0.699 AC: 3315 AN: 4740

European-Finnish (FIN) AF: 0.927 AC: 8840 AN: 9532

Middle Eastern (MID) AF: 0.914 AC: 265 AN: 290

European-Non Finnish (NFE) AF: 0.921 AC: 62220 AN: 67522

Other (OTH) AF: 0.916 AC: 1915 AN: 2090

Alfa AF: 0.905 Hom.: 55566

Bravo AF: 0.922

Asia WGS AF: 0.698 AC: 2416 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	4.5
DANN	Benign	0.27
PhyloP100		0.80
Mutation Taster		=100/0	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: rs2853228; hg19: chr8-103227082;