2-10124835-A-G

Position:

• chr2-10124835-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

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]

ACMG classification

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	UniProt
RRM2	NM_001034.4	c.554A>G	p.Lys185Arg	missense_variant	5/10	ENST00000304567.10
RRM2	NM_001165931.1	c.734A>G	p.Lys245Arg	missense_variant	5/10
RRM2	NR_164157.1	n.614A>G		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM2	ENST00000304567.10	c.554A>G	p.Lys185Arg	missense_variant	5/10	1	NM_001034.4	P1

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The 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

Other links and lift over

dbSNP: rs1662747428; hg19: chr2-10264962;