2-10124835-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001034.4(RRM2):​c.554A>G​(p.Lys185Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

RRM2
NM_001034.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.22
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.39391354).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RRM2NM_001034.4 linkuse as main transcriptc.554A>G p.Lys185Arg missense_variant 5/10 ENST00000304567.10 NP_001025.1
RRM2NM_001165931.1 linkuse as main transcriptc.734A>G p.Lys245Arg missense_variant 5/10 NP_001159403.1
RRM2NR_164157.1 linkuse as main transcriptn.614A>G non_coding_transcript_exon_variant 5/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RRM2ENST00000304567.10 linkuse as main transcriptc.554A>G p.Lys185Arg missense_variant 5/101 NM_001034.4 ENSP00000302955 P1P31350-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

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 GeneticsJan 22, 2024The c.734A>G (p.K245R) alteration is located in exon 5 (coding exon 5) of the RRM2 gene. This alteration results from a A to G substitution at nucleotide position 734, causing the lysine (K) at amino acid position 245 to be replaced by an arginine (R). 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
0.078
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
23
DANN
Benign
0.74
DEOGEN2
Uncertain
0.50
D;.;.;D;T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
.;.;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.39
T;T;T;T;T
MetaSVM
Uncertain
0.26
D
MutationAssessor
Benign
0.27
N;.;.;N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.73
.;N;.;N;N
REVEL
Uncertain
0.39
Sift
Benign
0.23
.;T;.;T;T
Sift4G
Benign
0.33
.;T;T;T;T
Polyphen
0.0010
B;.;.;B;.
Vest4
0.74, 0.74, 0.74
MutPred
0.40
Loss of ubiquitination at K185 (P = 0.011);.;.;Loss of ubiquitination at K185 (P = 0.011);.;
MVP
0.56
MPC
1.6
ClinPred
0.96
D
GERP RS
3.9
Varity_R
0.31
gMVP
0.82

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.

Other links and lift over

dbSNP: rs1662747428; hg19: chr2-10264962; API