dbSNP rs16991615: MCM8:p.Glu341Lys (chr20-5967581-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032485.6(MCM8):c.1021G>A(p.Glu341Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0559 in 1,610,584 control chromosomes in the GnomAD database, including 2,815 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.041 ( 182 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2633 hom. )

Consequence

MCM8
NM_032485.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.99

Publications

120 publications found

Variant links:

Genes affected

MCM8 (HGNC:16147): (minichromosome maintenance 8 homologous recombination repair factor) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the mini-chromosome maintenance proteins is a key component of the pre-replication complex and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the mini-chromosome maintenance proteins. The encoded protein may interact with other mini-chromosome maintenance proteins and play a role in DNA replication. This gene may be associated with length of reproductive lifespan and menopause. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

MCM8 Gene-Disease associations (from GenCC):

premature ovarian failure 10
Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MCM8 links:

ENSG00000286235 (HGNC:):

ENSG00000286235 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018333793).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6 link	c.1021G>A	p.Glu341Lys	missense_variant	Exon 9 of 19	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4 link	c.1021G>A	p.Glu341Lys	missense_variant	Exon 9 of 19	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1 link	c.1021G>A	p.Glu341Lys	missense_variant	Exon 9 of 24			ENSP00000498784.1

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6297

AN:

152174

Hom.:

182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0614

Gnomad OTH

AF:

0.0602

GnomAD2 exomes

AF:

0.0451

AC:

11287

AN:

250206

AF XY:

0.0463

show subpopulations

Gnomad AFR exome

AF:

0.00936

Gnomad AMR exome

AF:

0.0389

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0637

Gnomad OTH exome

AF:

0.0585

GnomAD4 exome

AF:

0.0574

AC:

83700

AN:

1458292

Hom.:

2633

Cov.:

AF XY:

0.0567

AC XY:

41108

AN XY:

724802

show subpopulations

African (AFR)

AF:

0.00841

AC:

281

AN:

33432

American (AMR)

AF:

0.0391

AC:

1742

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2819

AN:

26066

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39590

South Asian (SAS)

AF:

0.0268

AC:

2298

AN:

85850

European-Finnish (FIN)

AF:

0.0204

AC:

1089

AN:

53386

Middle Eastern (MID)

AF:

0.0436

AC:

251

AN:

5760

European-Non Finnish (NFE)

AF:

0.0648

AC:

71922

AN:

1109446

Other (OTH)

AF:

0.0547

AC:

3296

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3466

6932

10397

13863

17329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2614

5228

7842

10456

13070

<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:

0.0414

AC:

6298

AN:

152292

Hom.:

182

Cov.:

AF XY:

0.0398

AC XY:

2965

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0109

AC:

451

AN:

41552

American (AMR)

AF:

0.0564

AC:

863

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

349

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0218

AC:

105

AN:

4824

European-Finnish (FIN)

AF:

0.0170

AC:

181

AN:

10622

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0614

AC:

4174

AN:

68022

Other (OTH)

AF:

0.0595

AC:

126

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

312

624

935

1247

1559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0583

Hom.:

1316

Bravo

AF:

0.0436

TwinsUK

AF:

0.0601

AC:

223

ALSPAC

AF:

0.0612

AC:

236

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.0692

AC:

595

ExAC

AF:

0.0450

AC:

5461

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0637

EpiControl

AF:

0.0682

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T;.;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D;.;T

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.97

L;L;L;L;L

PhyloP100

6.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.9

N;N;N;.;N

REVEL

Benign

0.048

Sift

Benign

0.19

T;T;T;.;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.32

B;B;.;B;B

Vest4

0.34

MPC

0.25

ClinPred

0.017

GERP RS

5.0

Varity_R

0.10

gMVP

0.54

Mutation Taster

=96/4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over