3-127604987-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BA1

The NM_004526.4(MCM2):c.504C>T(p.Ile168Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,613,788 control chromosomes in the GnomAD database, including 431,880 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 35402 hom., cov: 33)

Exomes 𝑓: 0.73 ( 396478 hom. )

Consequence

MCM2
NM_004526.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.08

Publications

30 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 -17 ACMG points.

BP6

Variant 3-127604987-C-T is Benign according to our data. Variant chr3-127604987-C-T is described in ClinVar as Benign. ClinVar VariationId is 508098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM2	NM_004526.4 link	c.504C>T	p.Ile168Ile	synonymous_variant	Exon 4 of 16	ENST00000265056.12	NP_004517.2	P49736
MCM2	XM_024453531.2 link	c.477C>T	p.Ile159Ile	synonymous_variant	Exon 4 of 16		XP_024309299.1
MCM2	NR_073375.2 link	n.579C>T		non_coding_transcript_exon_variant	Exon 4 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM2	ENST00000265056.12 link	c.504C>T	p.Ile168Ile	synonymous_variant	Exon 4 of 16	1	NM_004526.4	ENSP00000265056.7		P49736

Frequencies

GnomAD3 genomes

AF:

0.674

AC:

102530

AN:

152018

Hom.:

35397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.537

Gnomad AMI

AF:

0.619

Gnomad AMR

AF:

0.653

Gnomad ASJ

AF:

0.750

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.567

Gnomad FIN

AF:

0.750

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.691

GnomAD2 exomes

AF:

0.685

AC:

171734

AN:

250872

AF XY:

0.689

show subpopulations

Gnomad AFR exome

AF:

0.530

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.752

Gnomad EAS exome

AF:

0.656

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.762

Gnomad OTH exome

AF:

0.716

GnomAD4 exome

AF:

0.734

AC:

1072127

AN:

1461652

Hom.:

396478

Cov.:

AF XY:

0.730

AC XY:

531130

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.525

AC:

17575

AN:

33480

American (AMR)

AF:

0.564

AC:

25199

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.745

AC:

19474

AN:

26132

East Asian (EAS)

AF:

0.657

AC:

26081

AN:

39698

South Asian (SAS)

AF:

0.581

AC:

50099

AN:

86256

European-Finnish (FIN)

AF:

0.747

AC:

39855

AN:

53344

Middle Eastern (MID)

AF:

0.744

AC:

4294

AN:

5768

European-Non Finnish (NFE)

AF:

0.761

AC:

846116

AN:

1111890

Other (OTH)

AF:

0.719

AC:

43434

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

19469

38937

58406

77874

97343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20274

40548

60822

81096

101370

<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:

0.674

AC:

102565

AN:

152136

Hom.:

35402

Cov.:

AF XY:

0.671

AC XY:

49940

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.536

AC:

22238

AN:

41482

American (AMR)

AF:

0.652

AC:

9978

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

2602

AN:

3470

East Asian (EAS)

AF:

0.647

AC:

3339

AN:

5164

South Asian (SAS)

AF:

0.568

AC:

2741

AN:

4824

European-Finnish (FIN)

AF:

0.750

AC:

7940

AN:

10588

Middle Eastern (MID)

AF:

0.728

AC:

214

AN:

294

European-Non Finnish (NFE)

AF:

0.757

AC:

51498

AN:

67992

Other (OTH)

AF:

0.687

AC:

1452

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1650

3300

4950

6600

8250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.723

Hom.:

123509

Bravo

AF:

0.661

Asia WGS

AF:

0.611

AC:

2125

AN:

3478

EpiCase

AF:

0.767

EpiControl

AF:

0.770

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

May 09, 2017

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. -

Autosomal dominant nonsyndromic hearing loss 70

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

3.3

(source)

DANN

Benign

0.92

PhyloP100

-1.1

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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