Genetic Variant RRM2:c.570-439G>A (chr2-10126436-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001034.4(RRM2):c.570-439G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 159,448 control chromosomes in the GnomAD database, including 43,742 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 0.73 ( 42013 hom., cov: 32)

Exomes 𝑓: 0.67 ( 1729 hom. )

Consequence

RRM2
NM_001034.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.09

Publications

12 publications found

Variant links:

Genes affected

RRM2 (HGNC:10452): (ribonucleotide reductase regulatory subunit M2) This gene encodes one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini. Related pseudogenes have been identified on chromosomes 1 and X. [provided by RefSeq, Sep 2009]

RRM2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RRM2	NM_001034.4	MANE Select	c.570-439G>A	intron	N/A	NP_001025.1
RRM2	NM_001165931.1		c.750-439G>A	intron	N/A	NP_001159403.1
RRM2	NR_164157.1		n.630-439G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RRM2	ENST00000304567.10	TSL:1 MANE Select	c.570-439G>A	intron	N/A	ENSP00000302955.4
RRM2	ENST00000360566.6	TSL:1	c.750-439G>A	intron	N/A	ENSP00000353770.2
RRM2	ENST00000615152.5	TSL:1	c.420-439G>A	intron	N/A	ENSP00000484183.2

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

111289

AN:

152006

Hom.:

41971

Cov.:

show subpopulations

Gnomad AFR

AF:

0.892

Gnomad AMI

AF:

0.748

Gnomad AMR

AF:

0.620

Gnomad ASJ

AF:

0.793

Gnomad EAS

AF:

0.337

Gnomad SAS

AF:

0.597

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.778

Gnomad NFE

AF:

0.711

Gnomad OTH

AF:

0.739

GnomAD4 exome

AF:

0.673

AC:

4926

AN:

7324

Hom.:

1729

AF XY:

0.669

AC XY:

2565

AN XY:

3834

show subpopulations

African (AFR)

AF:

0.911

AC:

153

AN:

168

American (AMR)

AF:

0.545

AC:

384

AN:

704

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

140

AN:

170

East Asian (EAS)

AF:

0.302

AC:

AN:

232

South Asian (SAS)

AF:

0.607

AC:

312

AN:

514

European-Finnish (FIN)

AF:

0.610

AC:

133

AN:

218

Middle Eastern (MID)

AF:

0.750

AC:

AN:

European-Non Finnish (NFE)

AF:

0.702

AC:

3494

AN:

4976

Other (OTH)

AF:

0.701

AC:

234

AN:

334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

166

250

333

416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.732

AC:

111381

AN:

152124

Hom.:

42013

Cov.:

AF XY:

0.721

AC XY:

53649

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.892

AC:

37046

AN:

41532

American (AMR)

AF:

0.619

AC:

9452

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.793

AC:

2750

AN:

3470

East Asian (EAS)

AF:

0.337

AC:

1741

AN:

5164

South Asian (SAS)

AF:

0.597

AC:

2880

AN:

4828

European-Finnish (FIN)

AF:

0.634

AC:

6693

AN:

10552

Middle Eastern (MID)

AF:

0.779

AC:

229

AN:

294

European-Non Finnish (NFE)

AF:

0.711

AC:

48352

AN:

67996

Other (OTH)

AF:

0.739

AC:

1556

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1432

2864

4295

5727

7159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.718

Hom.:

65940

Bravo

AF:

0.736

Asia WGS

AF:

0.509

AC:

1771

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.32

(source)

DANN

Benign

0.78

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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