20-5954739-T-C

Variant names:

• chr20-5954739-T-C
• rs236114
• NM_032485.6:c.336+49T>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.336+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 1,115,924 control chromosomes in the GnomAD database, including 374,089 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 0.84 (54444 hom., cov: 33)
  • Exomes 𝑓: 0.81 (319645 hom.)
• Consequence: MCM8 NM_032485.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.223
• Publications: 37 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6	c.336+49T>C		intron_variant	Intron 4 of 18	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.336+49T>C		intron_variant	Intron 4 of 18	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.336+49T>C		intron_variant	Intron 4 of 23			ENSP00000498784.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128301 AN: 152144 Hom.: 54387 Cov.: 33

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.832

Gnomad ASJ AF: 0.772

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.835

GnomAD2 exomes AF: 0.835 AC: 197574 AN: 236494 AF XY: 0.828

Gnomad AFR exome AF: 0.916

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.767

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.815

GnomAD4 exome AF: 0.813 AC: 783106 AN: 963662 Hom.: 319645 Cov.: 12 AF XY: 0.811 AC XY: 404117 AN XY: 498140

African (AFR) AF: 0.913 AC: 21605 AN: 23660

American (AMR) AF: 0.866 AC: 36540 AN: 42172

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 16989 AN: 22248

East Asian (EAS) AF: 0.999 AC: 37174 AN: 37212

South Asian (SAS) AF: 0.816 AC: 60447 AN: 74106

European-Finnish (FIN) AF: 0.854 AC: 41405 AN: 48494

Middle Eastern (MID) AF: 0.840 AC: 4025 AN: 4794

European-Non Finnish (NFE) AF: 0.793 AC: 528749 AN: 667152

Other (OTH) AF: 0.825 AC: 36172 AN: 43824

GnomAD4 genome AF: 0.843 AC: 128417 AN: 152262 Hom.: 54444 Cov.: 33 AF XY: 0.846 AC XY: 62974 AN XY: 74444

African (AFR) AF: 0.913 AC: 37927 AN: 41546

American (AMR) AF: 0.832 AC: 12718 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 2680 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5172 AN: 5188

South Asian (SAS) AF: 0.813 AC: 3922 AN: 4822

European-Finnish (FIN) AF: 0.865 AC: 9172 AN: 10600

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 54037 AN: 68022

Other (OTH) AF: 0.837 AC: 1771 AN: 2116

Alfa AF: 0.808 Hom.: 236118

Bravo AF: 0.848

Asia WGS AF: 0.918 AC: 3191 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.0
DANN	Benign	0.62
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs236114; hg19: chr20-5935385;