3-127599350-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004526.4(MCM2):c.39C>G(p.Ser13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM2 NM_004526.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0280

Genes affected

MCM2 (HGNC:6944): (minichromosome maintenance complex component 2) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MCM2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24071404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM2	NM_004526.4	c.39C>G	p.Ser13Arg	missense_variant	2/16	ENST00000265056.12
MCM2	XM_024453531.2	c.12C>G	p.Ser4Arg	missense_variant	2/16
MCM2	NR_073375.2	n.95C>G		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM2	ENST00000265056.12	c.39C>G	p.Ser13Arg	missense_variant	2/16	1	NM_004526.4	P1
MCM2	ENST00000480910.1	c.12C>G	p.Ser4Arg	missense_variant	2/3	2
MCM2	ENST00000472731.1	c.12C>G	p.Ser4Arg	missense_variant	1/2	2
MCM2	ENST00000474964.5	c.39C>G	p.Ser13Arg	missense_variant, NMD_transcript_variant	2/16	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2022

This variant has not been reported in the literature in individuals affected with MCM2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 13 of the MCM2 protein (p.Ser13Arg). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.051	T;.;T
Eigen	Benign	0.094
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;D
Sift4G	Benign	0.19	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.48
MutPred		0.26		Gain of MoRF binding (P = 0.0081);.;.;
MVP		0.52
MPC		0.50
ClinPred		0.58	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-127318193;