NM_032485.6:c.2258C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032485.6(MCM8):​c.2258C>G​(p.Ser753Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

MCM8
NM_032485.6 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.44
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-AS1 (HGNC:51230): (MCM8 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3818483).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MCM8NM_032485.6 linkc.2258C>G p.Ser753Cys missense_variant Exon 18 of 19 ENST00000610722.4 NP_115874.3 Q9UJA3-1B4DN82

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MCM8ENST00000610722.4 linkc.2258C>G p.Ser753Cys missense_variant Exon 18 of 19 1 NM_032485.6 ENSP00000478141.1 Q9UJA3-1
ENSG00000286235ENST00000652720.1 linkc.2258C>G p.Ser753Cys missense_variant Exon 18 of 24 ENSP00000498784.1 A0A494C100

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2258C>G (p.S753C) alteration is located in exon 18 (coding exon 17) of the MCM8 gene. This alteration results from a C to G substitution at nucleotide position 2258, causing the serine (S) at amino acid position 753 to be replaced by a cysteine (C). 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
0.12
BayesDel_addAF
Benign
-0.028
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Benign
0.055
.;T;.;T;.
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;.;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.38
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
.;M;.;M;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-2.1
N;N;N;.;N
REVEL
Benign
0.19
Sift
Benign
0.16
T;T;T;.;T
Sift4G
Benign
0.15
T;T;T;T;T
Polyphen
0.020
B;B;.;B;B
Vest4
0.68
MutPred
0.44
.;Loss of disorder (P = 0.0143);.;Loss of disorder (P = 0.0143);.;
MVP
0.30
MPC
0.57
ClinPred
0.85
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-5974169; API