Genetic Variant MCM8:c.336+113C>G (chr20-5954803-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032485.6(MCM8):c.336+113C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000201 in 498,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

MCM8
NM_032485.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0950

Publications

2 publications found

Variant links:

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

MCM8 links:

ENSG00000286235 (HGNC:):

ENSG00000286235 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCM8	NM_032485.6	MANE Select	c.336+113C>G	intron	N/A	NP_115874.3
MCM8	NM_001281521.2		c.336+113C>G	intron	N/A	NP_001268450.1
MCM8	NM_001281520.2		c.336+113C>G	intron	N/A	NP_001268449.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCM8	ENST00000610722.4	TSL:1 MANE Select	c.336+113C>G	intron	N/A	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1		c.336+113C>G	intron	N/A	ENSP00000498784.1
MCM8	ENST00000378886.6	TSL:1	c.336+113C>G	intron	N/A	ENSP00000368164.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000201

AC:

AN:

498002

Hom.:

AF XY:

0.00

AC XY:

AN XY:

263312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13644

American (AMR)

AF:

0.00

AC:

AN:

20324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14404

East Asian (EAS)

AF:

0.00

AC:

AN:

32040

South Asian (SAS)

AF:

0.00

AC:

AN:

46984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3716

European-Non Finnish (NFE)

AF:

0.00000326

AC:

AN:

306322

Other (OTH)

AF:

0.00

AC:

AN:

27674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.6

(source)

DANN

Benign

0.54

PhyloP100

-0.095

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over