20-5994321-T-C

Variant names:

• chr20-5994321-T-C
• rs1255666023
• NM_032485.6:c.2453T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_032485.6(MCM8):​c.2453T>C​(p.Ile818Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,602,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032485.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	NM_032485.6	MANE Select	c.2453T>C	p.Ile818Thr	missense	Exon 19 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.2573T>C	p.Ile858Thr	missense	Exon 19 of 19	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.2453T>C	p.Ile818Thr	missense	Exon 19 of 19	NP_001268449.1	Q9UJA3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	ENST00000610722.4	TSL:1 MANE Select	c.2453T>C	p.Ile818Thr	missense	Exon 19 of 19	ENSP00000478141.1	Q9UJA3-1
	MCM8	ENST00000378886.6	TSL:1	c.2573T>C	p.Ile858Thr	missense	Exon 19 of 19	ENSP00000368164.2	Q9UJA3-4
	MCM8	ENST00000378896.7	TSL:1	c.2453T>C	p.Ile818Thr	missense	Exon 19 of 19	ENSP00000368174.3	Q9UJA3-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000621 AC: 9 AN: 1449956 Hom.: 0 Cov.: 30 AF XY: 0.00000555 AC XY: 4 AN XY: 721276

African (AFR) AF: 0.00 AC: 0 AN: 32636

American (AMR) AF: 0.00 AC: 0 AN: 42128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 38896

South Asian (SAS) AF: 0.00 AC: 0 AN: 84100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000813 AC: 9 AN: 1107588

Other (OTH) AF: 0.00 AC: 0 AN: 59748

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.80	P
Vest4		0.68
MutPred		0.76		Loss of stability (P = 0.0162)
MVP		0.55
MPC		0.31
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.79
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs1255666023; hg19: chr20-5974967;