3-127599363-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004526.4(MCM2):c.52C>T(p.Arg18Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MCM2
NM_004526.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.608

Variant links:

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]

MCM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04967165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MCM2	NM_004526.4 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant	2/16	ENST00000265056.12
MCM2	XM_024453531.2 linkuse as main transcript	c.25C>T	p.Arg9Trp	missense_variant	2/16
MCM2	NR_073375.2 linkuse as main transcript	n.108C>T		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MCM2	ENST00000265056.12 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant	2/16	1	NM_004526.4	P1
MCM2	ENST00000480910.1 linkuse as main transcript	c.25C>T	p.Arg9Trp	missense_variant	2/3	2
MCM2	ENST00000472731.1 linkuse as main transcript	c.25C>T	p.Arg9Trp	missense_variant	1/2	2
MCM2	ENST00000474964.5 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant, NMD_transcript_variant	2/16	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251420

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000205

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 18 of the MCM2 protein (p.Arg18Trp). This variant is present in population databases (rs775610133, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MCM2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.050

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.2

N;D;D

REVEL

Benign

0.087

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.13

B;.;.

Vest4

0.32

MutPred

0.23

Loss of glycosylation at P14 (P = 0.0649);.;.;

MVP

0.30

MPC

0.54

ClinPred

0.12

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.062

gMVP

0.29

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

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