20-5957171-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032485.6(MCM8):c.532C>G(p.Gln178Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MCM8
NM_032485.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08114639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM8	NM_032485.6 linkuse as main transcript	c.532C>G	p.Gln178Glu	missense_variant	6/19	ENST00000610722.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM8	ENST00000610722.4 linkuse as main transcript	c.532C>G	p.Gln178Glu	missense_variant	6/19	1	NM_032485.6	P1	Q9UJA3-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251220

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.532C>G (p.Q178E) alteration is located in exon 6 (coding exon 5) of the MCM8 gene. This alteration results from a C to G substitution at nucleotide position 532, causing the glutamine (Q) at amino acid position 178 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.11

Eigen_PC

Benign

0.096

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;T;T;.;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.081

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.68

N;N;N;N;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.50

N;N;N;.;N

REVEL

Benign

0.068

Sift

Benign

0.40

T;T;T;.;T

Sift4G

Benign

0.58

T;T;T;T;T

Polyphen

0.0

B;B;.;B;B

Vest4

0.28

MutPred

0.26

Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.29

MPC

0.15

ClinPred

0.11

GERP RS

4.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.14

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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