20-5980045-T-C

Variant names:

• chr20-5980045-T-C
• rs236106
• NM_032485.6:c.1537+2028T>C

Variant summary

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

The NM_032485.6(MCM8):​c.1537+2028T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 152,060 control chromosomes in the GnomAD database, including 15,248 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 0.37 (15248 hom., cov: 32)
• Consequence: MCM8 NM_032485.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 9 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 (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6	c.1537+2028T>C		intron_variant	Intron 13 of 18	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.1537+2028T>C		intron_variant	Intron 13 of 18	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.1537+2028T>C		intron_variant	Intron 13 of 23			ENSP00000498784.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56797 AN: 151942 Hom.: 15209 Cov.: 32

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.357

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.374 AC: 56896 AN: 152060 Hom.: 15248 Cov.: 32 AF XY: 0.372 AC XY: 27646 AN XY: 74322

African (AFR) AF: 0.758 AC: 31422 AN: 41454

American (AMR) AF: 0.296 AC: 4530 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3472

East Asian (EAS) AF: 0.425 AC: 2191 AN: 5158

South Asian (SAS) AF: 0.355 AC: 1710 AN: 4818

European-Finnish (FIN) AF: 0.210 AC: 2222 AN: 10576

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12985 AN: 67990

Other (OTH) AF: 0.353 AC: 744 AN: 2106

Alfa AF: 0.234 Hom.: 3674

Bravo AF: 0.399

Asia WGS AF: 0.399 AC: 1387 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.15
DANN	Benign	0.54
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs236106; hg19: chr20-5960691;