NM_032485.6:c.2258C>G

Variant names:

• chr20-5993523-C-G
• NM_032485.6:c.2258C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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]

ENSG00000286235 (HGNC:):

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

ACMG classification

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
MCM8	NM_032485.6	c.2258C>G	p.Ser753Cys	missense_variant	Exon 18 of 19	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.2258C>G	p.Ser753Cys	missense_variant	Exon 18 of 19	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.2258C>G	p.Ser753Cys	missense_variant	Exon 18 of 24			ENSP00000498784.1

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

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;