2-10123390-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001034.4(RRM2):ā€‹c.178A>Gā€‹(p.Thr60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

RRM2
NM_001034.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0150
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061879456).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RRM2NM_001034.4 linkuse as main transcriptc.178A>G p.Thr60Ala missense_variant 3/10 ENST00000304567.10
RRM2NM_001165931.1 linkuse as main transcriptc.358A>G p.Thr120Ala missense_variant 3/10
RRM2NR_164157.1 linkuse as main transcriptn.238A>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.178A>G p.Thr60Ala missense_variant 3/101 NM_001034.4 P1P31350-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.90e-7
AC:
1
AN:
1449658
Hom.:
0
Cov.:
32
AF XY:
0.00000139
AC XY:
1
AN XY:
721990
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

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 GeneticsApr 20, 2023The c.358A>G (p.T120A) 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 358, causing the threonine (T) at amino acid position 120 to be replaced by an alanine (A). 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
0.056
BayesDel_addAF
Benign
0.0057
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
0.54
DANN
Benign
0.86
DEOGEN2
Benign
0.11
T;.;.;T;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.095
N
LIST_S2
Benign
0.27
.;.;T;T;T
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.062
T;T;T;T;T
MetaSVM
Uncertain
-0.055
T
MutationAssessor
Benign
0.34
N;.;.;N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.31
.;N;.;N;N
REVEL
Benign
0.26
Sift
Benign
0.31
.;T;.;T;T
Sift4G
Benign
0.75
.;T;T;T;T
Polyphen
0.0
B;.;.;B;.
Vest4
0.064, 0.070, 0.062
MutPred
0.16
Loss of phosphorylation at T60 (P = 0.0017);.;.;Loss of phosphorylation at T60 (P = 0.0017);.;
MVP
0.43
MPC
0.67
ClinPred
0.049
T
GERP RS
-5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.019
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs1365971876; hg19: chr2-10263517; API