20-5993592-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6	c.2327C>G	p.Ala776Gly	missense_variant	Exon 18 of 19	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.2327C>G	p.Ala776Gly	missense_variant	Exon 18 of 19	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.2327C>G	p.Ala776Gly	missense_variant	Exon 18 of 24			ENSP00000498784.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;.
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D;T;.;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	.;L;.;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.18	T;T;T;.;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.087	B;B;.;B;B
Vest4		0.62
MutPred		0.32		.;Gain of helix (P = 0.0325);.;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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-5974238; COSMIC: COSV99495159;