dbSNP rs149523343: RRM2B:c.48+273G>T (chr8-102238554-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_001172477.1(RRM2B):c.264+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,512,064 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 23 hom. )

Consequence

RRM2B
NM_001172477.1 splice_region, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.270

Publications

0 publications found

Variant links:

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

RRM2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 8-102238554-C-A is Benign according to our data. Variant chr8-102238554-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00848 (1291/152304) while in subpopulation AFR AF = 0.03 (1247/41560). AF 95% confidence interval is 0.0286. There are 15 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172477.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RRM2B	NM_015713.5	MANE Select	c.48+273G>T	intron	N/A	NP_056528.2
RRM2B	NM_001172477.1		c.264+5G>T	splice_region intron	N/A	NP_001165948.1	Q7LG56-6
RRM2B	NM_001172478.2		c.48+273G>T	intron	N/A	NP_001165949.1	Q7LG56-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RRM2B	ENST00000251810.8	TSL:1 MANE Select	c.48+273G>T	intron	N/A	ENSP00000251810.3	Q7LG56-1
RRM2B	ENST00000395912.6	TSL:1	c.48+273G>T	intron	N/A	ENSP00000379248.2	Q7LG56-2
RRM2B	ENST00000519317.5	TSL:1	c.48+273G>T	intron	N/A	ENSP00000430641.1	Q7LG56-3

Frequencies

GnomAD3 genomes

AF:

0.00845

AC:

1286

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00179

AC:

237

AN:

132516

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0301

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000855

AC:

1163

AN:

1359760

Hom.:

Cov.:

AF XY:

0.000724

AC XY:

485

AN XY:

670228

show subpopulations

African (AFR)

AF:

0.0314

AC:

974

AN:

31018

American (AMR)

AF:

0.00149

AC:

AN:

34842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24496

East Asian (EAS)

AF:

0.00

AC:

AN:

34140

South Asian (SAS)

AF:

0.000154

AC:

AN:

77982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31518

Middle Eastern (MID)

AF:

0.000908

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.0000103

AC:

AN:

1063882

Other (OTH)

AF:

0.00193

AC:

109

AN:

56376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00848

AC:

1291

AN:

152304

Hom.:

Cov.:

AF XY:

0.00783

AC XY:

583

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0300

AC:

1247

AN:

41560

American (AMR)

AF:

0.00196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68026

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00463

Hom.:

Bravo

AF:

0.00963

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction;C2749861:Mitochondrial DNA depletion syndrome 8a;C2751319:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (1)

RRM2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

-0.27

PromoterAI

-0.095

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over