2-10122793-T-G

Variant names:

• chr2-10122793-T-G
• rs1130609
• ENST00000360566.6:c.175T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001165931.1(RRM2):​c.175T>G​(p.Ser59Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,583,810 control chromosomes in the GnomAD database, including 409,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (43577 hom., cov: 32)
  • Exomes 𝑓: 0.71 (365673 hom.)
• Consequence: RRM2 NM_001165931.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.10
• Publications: 43 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.731291E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165931.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2	NM_001034.4	MANE Select	c.-6T>G		5_prime_UTR	Exon 1 of 10	NP_001025.1	P31350-1
	RRM2	NM_001165931.1		c.175T>G	p.Ser59Ala	missense	Exon 1 of 10	NP_001159403.1	P31350-2
	RRM2	NR_164157.1		n.55T>G		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2	ENST00000360566.6	TSL:1	c.175T>G	p.Ser59Ala	missense	Exon 1 of 10	ENSP00000353770.2	P31350-2
	RRM2	ENST00000304567.10	TSL:1 MANE Select	c.-6T>G		5_prime_UTR	Exon 1 of 10	ENSP00000302955.4	P31350-1
	RRM2	ENST00000641198.1		c.-6T>G		5_prime_UTR	Exon 2 of 11	ENSP00000493399.1	P31350-1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113529 AN: 151998 Hom.: 43540 Cov.: 32

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.748

GnomAD2 exomes AF: 0.659 AC: 130679 AN: 198412 AF XY: 0.660

Gnomad AFR exome AF: 0.907

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.687

Gnomad EAS exome AF: 0.327

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.729

Gnomad OTH exome AF: 0.683

GnomAD4 exome AF: 0.710 AC: 1016035 AN: 1431694 Hom.: 365673 Cov.: 74 AF XY: 0.706 AC XY: 500808 AN XY: 709300

African (AFR) AF: 0.910 AC: 30068 AN: 33052

American (AMR) AF: 0.546 AC: 21614 AN: 39584

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 17357 AN: 25438

East Asian (EAS) AF: 0.348 AC: 13370 AN: 38458

South Asian (SAS) AF: 0.596 AC: 48748 AN: 81824

European-Finnish (FIN) AF: 0.717 AC: 35821 AN: 49936

Middle Eastern (MID) AF: 0.748 AC: 4278 AN: 5722

European-Non Finnish (NFE) AF: 0.731 AC: 803229 AN: 1098378

Other (OTH) AF: 0.701 AC: 41550 AN: 59302

GnomAD4 genome AF: 0.747 AC: 113617 AN: 152116 Hom.: 43577 Cov.: 32 AF XY: 0.739 AC XY: 54965 AN XY: 74360

African (AFR) AF: 0.904 AC: 37551 AN: 41542

American (AMR) AF: 0.622 AC: 9505 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2330 AN: 3472

East Asian (EAS) AF: 0.338 AC: 1735 AN: 5126

South Asian (SAS) AF: 0.581 AC: 2805 AN: 4826

European-Finnish (FIN) AF: 0.732 AC: 7746 AN: 10580

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.728 AC: 49503 AN: 67966

Other (OTH) AF: 0.748 AC: 1578 AN: 2110

Alfa AF: 0.722 Hom.: 80515

Bravo AF: 0.745

TwinsUK AF: 0.733 AC: 2718

ALSPAC AF: 0.743 AC: 2865

ESP6500AA AF: 0.891 AC: 3831

ESP6500EA AF: 0.714 AC: 6080

ExAC AF: 0.632 AC: 73516

Asia WGS AF: 0.508 AC: 1767 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.9
DANN	Benign	0.76
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.095	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.90	T
PhyloP100		-2.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.15	T
Vest4		0.010
MPC		0.57
ClinPred		0.0061	T
GERP RS		-3.4
PromoterAI		0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.042
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1130609; hg19: chr2-10262920; COSMIC: COSV58815817; COSMIC: COSV58815817;