Genetic Variant NM_001034.4:c.596C>T (chr2-10126901-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001034.4(RRM2):c.596C>T(p.Thr199Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,770 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RRM2
NM_001034.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.71

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2	NM_001034.4 link	c.596C>T	p.Thr199Met	missense_variant	Exon 6 of 10	ENST00000304567.10	NP_001025.1	P31350-1
RRM2	NM_001165931.1 link	c.776C>T	p.Thr259Met	missense_variant	Exon 6 of 10		NP_001159403.1	P31350-2
RRM2	NR_164157.1 link	n.656C>T		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.596C>T	p.Thr199Met	missense_variant	Exon 6 of 10	1	NM_001034.4	ENSP00000302955.4		P31350-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251384

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727188

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776C>T (p.T259M) alteration is located in exon 6 (coding exon 6) of the RRM2 gene. This alteration results from a C to T substitution at nucleotide position 776, causing the threonine (T) at amino acid position 259 to be replaced by a methionine (M). 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

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;.;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;.;H;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.4

.;D;.;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;D;.;D;D

Sift4G

Pathogenic

0.0010

.;D;D;D;D

Polyphen

1.0

D;.;.;D;.

Vest4

0.85, 0.85, 0.85

MutPred

0.55

Gain of catalytic residue at T199 (P = 0.0221);.;.;Gain of catalytic residue at T199 (P = 0.0221);.;

MVP

0.92

MPC

1.7

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.83

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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