chr20-5967581-G-A

Variant names:

• chr20-5967581-G-A
• rs16991615
• NM_032485.6:c.1021G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.99
• Publications: 120 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]

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

ENSG00000286235 (HGNC:):

ACMG classification

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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	NM_032485.6	MANE Select	c.1021G>A	p.Glu341Lys	missense	Exon 9 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.1021G>A	p.Glu341Lys	missense	Exon 9 of 19	NP_001268450.1
	MCM8	NM_001281520.2		c.1021G>A	p.Glu341Lys	missense	Exon 9 of 19	NP_001268449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	ENST00000610722.4	TSL:1 MANE Select	c.1021G>A	p.Glu341Lys	missense	Exon 9 of 19	ENSP00000478141.1
	ENSG00000286235	ENST00000652720.1		c.1021G>A	p.Glu341Lys	missense	Exon 9 of 24	ENSP00000498784.1
	MCM8	ENST00000378886.6	TSL:1	c.1021G>A	p.Glu341Lys	missense	Exon 9 of 19	ENSP00000368164.2

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6297 AN: 152174 Hom.: 182 Cov.: 32

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

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.: 31 AF XY: 0.0567 AC XY: 41108 AN XY: 724802

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: 2 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

GnomAD4 genome AF: 0.0414 AC: 6298 AN: 152292 Hom.: 182 Cov.: 32 AF XY: 0.0398 AC XY: 2965 AN XY: 74492

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: 0 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: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0614 AC: 4174 AN: 68022

Other (OTH) AF: 0.0595 AC: 126 AN: 2116

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: 53

ESP6500EA AF: 0.0692 AC: 595

ExAC AF: 0.0450 AC: 5461

Asia WGS AF: 0.00895 AC: 32 AN: 3478

EpiCase AF: 0.0637

EpiControl AF: 0.0682

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.048
Sift	Benign	0.19	T
Sift4G	Benign	0.17	T
Polyphen		0.32	B
Vest4		0.34
MPC		0.25
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.10
gMVP		0.54
Mutation Taster		=96/4	polymorphism (auto)

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: rs16991615; hg19: chr20-5948227; COSMIC: COSV54512304; COSMIC: COSV54512304;