2-10123478-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001034.4(RRM2):ā€‹c.266A>Gā€‹(p.Asp89Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

RRM2
NM_001034.4 missense

Scores

11
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RRM2NM_001034.4 linkuse as main transcriptc.266A>G p.Asp89Gly missense_variant 3/10 ENST00000304567.10
RRM2NM_001165931.1 linkuse as main transcriptc.446A>G p.Asp149Gly missense_variant 3/10
RRM2NR_164157.1 linkuse as main transcriptn.326A>G non_coding_transcript_exon_variant 3/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RRM2ENST00000304567.10 linkuse as main transcriptc.266A>G p.Asp89Gly missense_variant 3/101 NM_001034.4 P1P31350-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461874
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727240
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2022The c.446A>G (p.D149G) alteration is located in exon 3 (coding exon 3) of the RRM2 gene. This alteration results from a A to G substitution at nucleotide position 446, causing the aspartic acid (D) at amino acid position 149 to be replaced by a glycine (G). 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
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;.;.;D;D
Eigen
Benign
0.063
Eigen_PC
Benign
0.020
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.97
.;.;D;D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
3.5
H;.;.;H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.9
.;D;.;D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.010
.;D;.;D;D
Sift4G
Uncertain
0.016
.;D;D;D;D
Polyphen
0.12
B;.;.;B;.
Vest4
0.61, 0.61, 0.60
MutPred
0.70
Gain of MoRF binding (P = 0.1202);.;.;Gain of MoRF binding (P = 0.1202);.;
MVP
0.92
MPC
1.1
ClinPred
0.98
D
GERP RS
4.1
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.71
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-10263605; COSMIC: COSV58816887; COSMIC: COSV58816887; API