20-5978314-T-C

Variant names:

• chr20-5978314-T-C
• rs236104
• NM_032485.6:c.1537+297T>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+297T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 138,402 control chromosomes in the GnomAD database, including 15,291 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 0.41 (15291 hom., cov: 32)
• Consequence: MCM8 NM_032485.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.454
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6	c.1537+297T>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+297T>C		intron_variant	Intron 13 of 18	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.1537+297T>C		intron_variant	Intron 13 of 23			ENSP00000498784.1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 56937 AN: 138286 Hom.: 15252 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.393

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

GnomAD4 genome AF: 0.412 AC: 57036 AN: 138402 Hom.: 15291 Cov.: 32 AF XY: 0.413 AC XY: 27715 AN XY: 67140

African (AFR) AF: 0.764 AC: 31461 AN: 41186

American (AMR) AF: 0.349 AC: 4535 AN: 13002

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 829 AN: 3120

East Asian (EAS) AF: 0.483 AC: 2191 AN: 4538

South Asian (SAS) AF: 0.397 AC: 1735 AN: 4372

European-Finnish (FIN) AF: 0.267 AC: 2226 AN: 8352

Middle Eastern (MID) AF: 0.369 AC: 99 AN: 268

European-Non Finnish (NFE) AF: 0.214 AC: 13042 AN: 60864

Other (OTH) AF: 0.390 AC: 748 AN: 1916

Alfa AF: 0.317 Hom.: 1788

Bravo AF: 0.399

Asia WGS AF: 0.401 AC: 1393 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.60
PhyloP100		-0.45
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: rs236104; hg19: chr20-5958960;