20-5993592-C-G

Variant names:

• chr20-5993592-C-G
• rs200761922
• NM_032485.6:c.2327C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032485.6(MCM8):​c.2327C>G​(p.Ala776Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A776V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• Publications: 0 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]

ENSG00000286235 (HGNC:):

MCM8-AS1 (HGNC:51230): (MCM8 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2327C>G	p.Ala776Gly	missense	Exon 18 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.2447C>G	p.Ala816Gly	missense	Exon 18 of 19	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.2327C>G	p.Ala776Gly	missense	Exon 18 of 19	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.2327C>G	p.Ala776Gly	missense	Exon 18 of 19	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.2327C>G	p.Ala776Gly	missense	Exon 18 of 24	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.2447C>G	p.Ala816Gly	missense	Exon 18 of 19	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459994 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726312

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110726

Other (OTH) AF: 0.00 AC: 0 AN: 60282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Polyphen		0.087	B
Vest4		0.62
MutPred		0.32		Gain of helix (P = 0.0325)
MVP		0.32
MPC		0.16
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.43
gMVP		0.54
Mutation Taster		=49/51	disease causing

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: rs200761922; hg19: chr20-5974238; COSMIC: COSV99495159;