Genetic Variant RRM2:p.Ser59Ala (chr2-10122793-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000360566.6(RRM2):c.175T>G(p.Ser59Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,583,810 control chromosomes in the GnomAD database, including 409,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 43577 hom., cov: 32)

Exomes 𝑓: 0.71 ( 365673 hom. )

Consequence

RRM2
ENST00000360566.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.10

Publications

43 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=8.731291E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2	NM_001034.4 link	c.-6T>G		5_prime_UTR_variant	Exon 1 of 10	ENST00000304567.10	NP_001025.1	P31350-1
RRM2	NM_001165931.1 link	c.175T>G	p.Ser59Ala	missense_variant	Exon 1 of 10		NP_001159403.1	P31350-2
RRM2	NR_164157.1 link	n.55T>G		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2	ENST00000304567.10 link	c.-6T>G		5_prime_UTR_variant	Exon 1 of 10	1	NM_001034.4	ENSP00000302955.4		P31350-1

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113529

AN:

151998

Hom.:

43540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.904

Gnomad AMI

AF:

0.714

Gnomad AMR

AF:

0.623

Gnomad ASJ

AF:

0.671

Gnomad EAS

AF:

0.338

Gnomad SAS

AF:

0.583

Gnomad FIN

AF:

0.732

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.728

Gnomad OTH

AF:

0.748

GnomAD2 exomes

AF:

0.659

AC:

130679

AN:

198412

AF XY:

0.660

show subpopulations

Gnomad AFR exome

AF:

0.907

Gnomad AMR exome

AF:

0.535

Gnomad ASJ exome

AF:

0.687

Gnomad EAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.717

Gnomad NFE exome

AF:

0.729

Gnomad OTH exome

AF:

0.683

GnomAD4 exome

AF:

0.710

AC:

1016035

AN:

1431694

Hom.:

365673

Cov.:

AF XY:

0.706

AC XY:

500808

AN XY:

709300

show subpopulations

African (AFR)

AF:

0.910

AC:

30068

AN:

33052

American (AMR)

AF:

0.546

AC:

21614

AN:

39584

Ashkenazi Jewish (ASJ)

AF:

0.682

AC:

17357

AN:

25438

East Asian (EAS)

AF:

0.348

AC:

13370

AN:

38458

South Asian (SAS)

AF:

0.596

AC:

48748

AN:

81824

European-Finnish (FIN)

AF:

0.717

AC:

35821

AN:

49936

Middle Eastern (MID)

AF:

0.748

AC:

4278

AN:

5722

European-Non Finnish (NFE)

AF:

0.731

AC:

803229

AN:

1098378

Other (OTH)

AF:

0.701

AC:

41550

AN:

59302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17899

35798

53698

71597

89496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19786

39572

59358

79144

98930

<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:

0.747

AC:

113617

AN:

152116

Hom.:

43577

Cov.:

AF XY:

0.739

AC XY:

54965

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.904

AC:

37551

AN:

41542

American (AMR)

AF:

0.622

AC:

9505

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.671

AC:

2330

AN:

3472

East Asian (EAS)

AF:

0.338

AC:

1735

AN:

5126

South Asian (SAS)

AF:

0.581

AC:

2805

AN:

4826

European-Finnish (FIN)

AF:

0.732

AC:

7746

AN:

10580

Middle Eastern (MID)

AF:

0.735

AC:

216

AN:

294

European-Non Finnish (NFE)

AF:

0.728

AC:

49503

AN:

67966

Other (OTH)

AF:

0.748

AC:

1578

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1422

2844

4267

5689

7111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.722

Hom.:

80515

Bravo

AF:

0.745

TwinsUK

AF:

0.733

AC:

2718

ALSPAC

AF:

0.743

AC:

2865

ESP6500AA

AF:

0.891

AC:

3831

ESP6500EA

AF:

0.714

AC:

6080

ExAC

AF:

0.632

AC:

73516

Asia WGS

AF:

0.508

AC:

1767

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

2.9

(source)

DANN

Benign

0.76

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.095

.;T

MetaRNN

Benign

8.7e-7

T;T

MetaSVM

Benign

-0.90

PhyloP100

-2.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.21

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

0.15

T;T

Vest4

0.010

MPC

0.57

ClinPred

0.0061

GERP RS

-3.4

PromoterAI

0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.042

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over