chr22-35406668-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006739.4(MCM5):c.539C>G(p.Thr180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,611,746 control chromosomes in the GnomAD database, including 5,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 385 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5120 hom. )

Consequence

MCM5
NM_006739.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.169

Publications

24 publications found

Variant links:

Genes affected

MCM5 (HGNC:6948): (minichromosome maintenance complex component 5) The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation. [provided by RefSeq, Jul 2008]

MCM5 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 8
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

MCM5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018073916).

BP6

Variant 22-35406668-C-G is Benign according to our data. Variant chr22-35406668-C-G is described in ClinVar as Benign. ClinVar VariationId is 1674156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM5	NM_006739.4 link	c.539C>G	p.Thr180Ser	missense_variant	Exon 5 of 17	ENST00000216122.9	NP_006730.2	P33992B1AHB0
MCM5	XM_006724242.5 link	c.539C>G	p.Thr180Ser	missense_variant	Exon 5 of 18		XP_006724305.1
MCM5	XM_047441366.1 link	c.539C>G	p.Thr180Ser	missense_variant	Exon 5 of 18		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9 link	c.539C>G	p.Thr180Ser	missense_variant	Exon 5 of 17	1	NM_006739.4	ENSP00000216122.3		P33992

Frequencies

GnomAD3 genomes

AF:

0.0615

AC:

9368

AN:

152206

Hom.:

385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0268

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.0758

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0864

Gnomad OTH

AF:

0.0660

GnomAD2 exomes

AF:

0.0633

AC:

15779

AN:

249334

AF XY:

0.0664

show subpopulations

Gnomad AFR exome

AF:

0.0246

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0267

Gnomad EAS exome

AF:

0.00288

Gnomad FIN exome

AF:

0.0948

Gnomad NFE exome

AF:

0.0836

Gnomad OTH exome

AF:

0.0685

GnomAD4 exome

AF:

0.0795

AC:

116059

AN:

1459422

Hom.:

5120

Cov.:

AF XY:

0.0799

AC XY:

58000

AN XY:

726150

show subpopulations

African (AFR)

AF:

0.0224

AC:

750

AN:

33478

American (AMR)

AF:

0.0289

AC:

1292

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

679

AN:

26132

East Asian (EAS)

AF:

0.00438

AC:

174

AN:

39700

South Asian (SAS)

AF:

0.0762

AC:

6576

AN:

86250

European-Finnish (FIN)

AF:

0.0946

AC:

4835

AN:

51116

Middle Eastern (MID)

AF:

0.0413

AC:

238

AN:

5758

European-Non Finnish (NFE)

AF:

0.0874

AC:

97188

AN:

1111900

Other (OTH)

AF:

0.0717

AC:

4327

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

5514

11027

16541

22054

27568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3494

6988

10482

13976

17470

<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:

0.0615

AC:

9371

AN:

152324

Hom.:

385

Cov.:

AF XY:

0.0613

AC XY:

4562

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0268

AC:

1115

AN:

41588

American (AMR)

AF:

0.0433

AC:

662

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3470

East Asian (EAS)

AF:

0.00482

AC:

AN:

5182

South Asian (SAS)

AF:

0.0763

AC:

368

AN:

4826

European-Finnish (FIN)

AF:

0.101

AC:

1077

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0864

AC:

5878

AN:

68026

Other (OTH)

AF:

0.0653

AC:

138

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

450

900

1351

1801

2251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0677

Hom.:

293

Bravo

AF:

0.0541

TwinsUK

AF:

0.0847

AC:

314

ALSPAC

AF:

0.0846

AC:

326

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.0855

AC:

735

ExAC

AF:

0.0657

AC:

7971

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

EpiCase

AF:

0.0792

EpiControl

AF:

0.0781

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MCM5-related disorder

Benign:1

Nov 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

0.065

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.043

T;T;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.42

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.0

N;.;.;.

PhyloP100

-0.17

PrimateAI

Benign

0.34

PROVEAN

Benign

0.12

N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.75

T;T;T;T

Sift4G

Benign

0.75

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.082

MutPred

0.25

Gain of helix (P = 0.0425);.;.;.;

MPC

0.32

ClinPred

0.0010

GERP RS

0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.036

gMVP

0.13

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