2-10122775-G-C

Variant names:

• chr2-10122775-G-C
• rs368001878
• ENST00000360566.6:c.157G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001165931.1(RRM2):​c.157G>C​(p.Ala53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RRM2 NM_001165931.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.16
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110670865).

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.-24G>C		5_prime_UTR	Exon 1 of 10	NP_001025.1	P31350-1
	RRM2	NM_001165931.1		c.157G>C	p.Ala53Pro	missense	Exon 1 of 10	NP_001159403.1	P31350-2
	RRM2	NR_164157.1		n.37G>C		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.157G>C	p.Ala53Pro	missense	Exon 1 of 10	ENSP00000353770.2	P31350-2
	RRM2	ENST00000304567.10	TSL:1 MANE Select	c.-24G>C		5_prime_UTR	Exon 1 of 10	ENSP00000302955.4	P31350-1
	RRM2	ENST00000641198.1		c.-24G>C		5_prime_UTR	Exon 2 of 11	ENSP00000493399.1	P31350-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416102 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 700146

African (AFR) AF: 0.00 AC: 0 AN: 32566

American (AMR) AF: 0.00 AC: 0 AN: 37208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25280

East Asian (EAS) AF: 0.00 AC: 0 AN: 37570

South Asian (SAS) AF: 0.00 AC: 0 AN: 80508

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089460

Other (OTH) AF: 0.00 AC: 0 AN: 58714

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.19
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.33	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.17	D
PhyloP100		-2.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.21
Sift	Benign	0.095	T
Sift4G	Benign	0.15	T
Vest4		0.069
MutPred		0.43		Gain of catalytic residue at A53 (P = 0.0267)
MVP		0.23
MPC		1.1
ClinPred		0.12	T
GERP RS		0.069
PromoterAI		-0.037	Neutral
gMVP		0.18
Mutation Taster		=300/0	polymorphism

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: rs368001878; hg19: chr2-10262902;