20-5954739-T-C

Position:

• chr20-5954739-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MCM8	NM_032485.6	c.336+49T>C		intron_variant		ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.336+49T>C		intron_variant		1	NM_032485.6	ENSP00000478141	P1

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

GnomAD3 exomes AF: 0.835 AC: 197574 AN: 236494 Hom.: 82997 AF XY: 0.828 AC XY: 106222 AN XY: 128274

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 SAS exome AF: 0.815

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

Gnomad4 AFR exome AF: 0.913

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.764

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.816

Gnomad4 FIN exome AF: 0.854

Gnomad4 NFE exome AF: 0.793

Gnomad4 OTH exome AF: 0.825

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

Gnomad4 AFR AF: 0.913

Gnomad4 AMR AF: 0.832

Gnomad4 ASJ AF: 0.772

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.813

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.794

Gnomad4 OTH AF: 0.837

Alfa AF: 0.798 Hom.: 111110

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs236114; hg19: chr20-5935385;