Genetic Variant RRM2:p.Ile197Val (chr2-10126894-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001034.4(RRM2):c.589A>G(p.Ile197Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RRM2
NM_001034.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.09

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2	NM_001034.4 link	c.589A>G	p.Ile197Val	missense_variant	Exon 6 of 10	ENST00000304567.10	NP_001025.1	P31350-1
RRM2	NM_001165931.1 link	c.769A>G	p.Ile257Val	missense_variant	Exon 6 of 10		NP_001159403.1	P31350-2
RRM2	NR_164157.1 link	n.649A>G		non_coding_transcript_exon_variant	Exon 6 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2	ENST00000304567.10 link	c.589A>G	p.Ile197Val	missense_variant	Exon 6 of 10	1	NM_001034.4	ENSP00000302955.4		P31350-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.769A>G (p.I257V) alteration is located in exon 6 (coding exon 6) of the RRM2 gene. This alteration results from a A to G substitution at nucleotide position 769, causing the isoleucine (I) at amino acid position 257 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;D;T

Eigen

Benign

0.087

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;.;T;T;T

M_CAP

Uncertain

0.097

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.6

L;.;.;L;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.77

.;N;.;N;N

REVEL

Uncertain

0.57

Sift

Benign

0.050

.;D;.;T;T

Sift4G

Benign

0.12

.;T;T;T;T

Polyphen

0.019

B;.;.;B;.

Vest4

0.26, 0.25, 0.26

MutPred

0.70

Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);.;

MVP

0.70

MPC

0.58

ClinPred

0.81

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over