rs454422

Variant names:

• chr20-5963047-C-A
• rs454422
• NM_032485.6:c.790-227C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-5963047-C-A
• chr20-5963047-C-G
• chr20-5963047-C-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.790-227C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,964 control chromosomes in the GnomAD database, including 14,865 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 (14865 hom., cov: 31)
• Consequence: MCM8 NM_032485.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 27 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032485.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	NM_032485.6	MANE Select	c.790-227C>A		intron	N/A	NP_115874.3
	MCM8	NM_001281521.2		c.790-227C>A		intron	N/A	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.790-227C>A		intron	N/A	NP_001268449.1	Q9UJA3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	ENST00000610722.4	TSL:1 MANE Select	c.790-227C>A		intron	N/A	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.790-227C>A		intron	N/A	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.790-227C>A		intron	N/A	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56340 AN: 151846 Hom.: 14824 Cov.: 31

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.354

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

GnomAD4 genome AF: 0.371 AC: 56442 AN: 151964 Hom.: 14865 Cov.: 31 AF XY: 0.370 AC XY: 27444 AN XY: 74254

African (AFR) AF: 0.746 AC: 30901 AN: 41448

American (AMR) AF: 0.296 AC: 4516 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 829 AN: 3466

East Asian (EAS) AF: 0.425 AC: 2195 AN: 5166

South Asian (SAS) AF: 0.359 AC: 1731 AN: 4816

European-Finnish (FIN) AF: 0.211 AC: 2223 AN: 10524

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13039 AN: 67960

Other (OTH) AF: 0.351 AC: 739 AN: 2108

Alfa AF: 0.257 Hom.: 20650

Bravo AF: 0.394

Asia WGS AF: 0.401 AC: 1394 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		0.12
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: rs454422; hg19: chr20-5943693;