rs606231343

Positions:

• chr20-5955211-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_032485.6(MCM8):​c.446C>G​(p.Pro149Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.58

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 20-5955211-C-G is Pathogenic according to our data. Variant chr20-5955211-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 161191.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM8	NM_032485.6	c.446C>G	p.Pro149Arg	missense_variant	5/19	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.446C>G	p.Pro149Arg	missense_variant	5/19	1	NM_032485.6	ENSP00000478141	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian failure 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2014

- -

not provided Other:1

not provided, no classification provided

literature only

SNPedia

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T;.;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.5	D;D;D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.97
MutPred		0.52		Loss of catalytic residue at P149 (P = 0.0596);Loss of catalytic residue at P149 (P = 0.0596);Loss of catalytic residue at P149 (P = 0.0596);Loss of catalytic residue at P149 (P = 0.0596);Loss of catalytic residue at P149 (P = 0.0596);
MVP		0.57
MPC		0.62
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs606231343; hg19: chr20-5935857;