3-127608466-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 70
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MCM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein
MCM2	NM_004526.4 link	c.1186G>A	p.Ala396Thr	missense_variant	Exon 7 of 16	ENST00000265056.12	NP_004517.2
MCM2	XM_024453531.2 link	c.1159G>A	p.Ala387Thr	missense_variant	Exon 7 of 16		XP_024309299.1
MCM2	NR_073375.2 link	n.1261G>A		non_coding_transcript_exon_variant	Exon 7 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM2	ENST00000265056.12 link	c.1186G>A	p.Ala396Thr	missense_variant	Exon 7 of 16	1	NM_004526.4	ENSP00000265056.7

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

GnomAD2 exomes

AF:

0.00804

AC:

2020

AN:

251380

AF XY:

0.00829

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 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

African (AFR)

AF:

0.00155

AC:

AN:

33480

American (AMR)

AF:

0.00443

AC:

198

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

794

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86258

European-Finnish (FIN)

AF:

0.00356

AC:

190

AN:

53396

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0125

AC:

13869

AN:

1112004

Other (OTH)

AF:

0.0102

AC:

615

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

870

1739

2609

3478

4348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00831

AC:

1266

AN:

152342

Hom.:

Cov.:

AF XY:

0.00796

AC XY:

593

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

41582

American (AMR)

AF:

0.00594

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

831

AN:

68032

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0114

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

Aug 10, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MCM2: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

6.2

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

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over