20-5954803-C-T

Variant names:

• chr20-5954803-C-T
• rs236115
• NM_032485.6:c.336+113C>T

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+113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 649,682 control chromosomes in the GnomAD database, including 12,452 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 0.23 (5679 hom., cov: 33)
  • Exomes 𝑓: 0.15 (6773 hom.)
• Consequence: MCM8 NM_032485.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 2 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6	c.336+113C>T		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+113C>T		intron_variant	Intron 4 of 18	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.336+113C>T		intron_variant	Intron 4 of 23			ENSP00000498784.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34571 AN: 152040 Hom.: 5665 Cov.: 33

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.150 AC: 74571 AN: 497524 Hom.: 6773 AF XY: 0.152 AC XY: 40106 AN XY: 263034

African (AFR) AF: 0.455 AC: 6194 AN: 13612

American (AMR) AF: 0.166 AC: 3366 AN: 20308

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 1808 AN: 14398

East Asian (EAS) AF: 0.157 AC: 5017 AN: 32016

South Asian (SAS) AF: 0.233 AC: 10925 AN: 46900

European-Finnish (FIN) AF: 0.166 AC: 5449 AN: 32860

Middle Eastern (MID) AF: 0.148 AC: 549 AN: 3716

European-Non Finnish (NFE) AF: 0.120 AC: 36607 AN: 306054

Other (OTH) AF: 0.168 AC: 4656 AN: 27660

GnomAD4 genome AF: 0.228 AC: 34625 AN: 152158 Hom.: 5679 Cov.: 33 AF XY: 0.227 AC XY: 16919 AN XY: 74394

African (AFR) AF: 0.463 AC: 19222 AN: 41490

American (AMR) AF: 0.161 AC: 2456 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 443 AN: 3472

East Asian (EAS) AF: 0.182 AC: 942 AN: 5184

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4822

European-Finnish (FIN) AF: 0.155 AC: 1645 AN: 10594

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8174 AN: 67996

Other (OTH) AF: 0.208 AC: 439 AN: 2112

Alfa AF: 0.189 Hom.: 541

Bravo AF: 0.236

Asia WGS AF: 0.227 AC: 792 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.70
PhyloP100		-0.095
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: rs236115; hg19: chr20-5935449; COSMIC: COSV107218941; COSMIC: COSV107218941;