3-127608466-G-A

Position:

chr3-127608466-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004526.4(MCM2):c.1186G>A(p.Ala396Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0107 in 1,614,204 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0083 ( 15 hom., cov: 32)

Exomes 𝑓: 0.011 ( 106 hom. )

Consequence

MCM2
NM_004526.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.17

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:

MCM2 (HGNC:):

MCM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008700162).

BP6

Variant 3-127608466-G-A is Benign according to our data. Variant chr3-127608466-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 508564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1266 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM2	NM_004526.4 linkuse as main transcript	c.1186G>A	p.Ala396Thr	missense_variant	7/16	ENST00000265056.12	NP_004517.2	P49736
MCM2	XM_024453531.2 linkuse as main transcript	c.1159G>A	p.Ala387Thr	missense_variant	7/16		XP_024309299.1
MCM2	NR_073375.2 linkuse as main transcript	n.1261G>A		non_coding_transcript_exon_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM2	ENST00000265056.12 linkuse as main transcript	c.1186G>A	p.Ala396Thr	missense_variant	7/16	1	NM_004526.4	ENSP00000265056.7		P49736

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1266

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00804

AC:

2020

AN:

251380

Hom.:

AF XY:

0.00829

AC XY:

1126

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00457

Gnomad ASJ exome

AF:

0.0318

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00235

Gnomad FIN exome

AF:

0.00351

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00864

GnomAD4 exome

AF:

0.0110

AC:

16025

AN:

1461862

Hom.:

106

Cov.:

AF XY:

0.0109

AC XY:

7931

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00443

Gnomad4 ASJ exome

AF:

0.0304

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00268

Gnomad4 FIN exome

AF:

0.00356

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00831

AC:

1266

AN:

152342

Hom.:

Cov.:

AF XY:

0.00796

AC XY:

593

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.00594

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.0122

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.00832

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00805

AC:

978

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MCM2: BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MCM2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0087

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

0.52

Vest4

0.76

MVP

0.46

MPC

0.37

ClinPred

0.0082

GERP RS

5.3

Varity_R

0.51

gMVP

0.56

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