20-5954646-G-C

Position:

• chr20-5954646-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032485.6(MCM8):​c.292G>C​(p.Ala98Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000881 in 1,611,166 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.70

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008928657).
• BP6: Variant 20-5954646-G-C is Benign according to our data. Variant chr20-5954646-G-C is described in ClinVar as [Benign]. Clinvar id is 784405.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00446 (680/152316) while in subpopulation AFR AF= 0.0148 (614/41560). AF 95% confidence interval is 0.0138. There are 6 homozygotes in gnomad4. There are 350 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM8	NM_032485.6	c.292G>C	p.Ala98Pro	missense_variant	4/19	ENST00000610722.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM8	ENST00000610722.4	c.292G>C	p.Ala98Pro	missense_variant	4/19	1	NM_032485.6	P1

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152198 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00126 AC: 315 AN: 250946 Hom.: 0 AF XY: 0.00105 AC XY: 142 AN XY: 135696

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000507 AC: 740 AN: 1458850 Hom.: 4 Cov.: 28 AF XY: 0.000467 AC XY: 339 AN XY: 725856

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000595

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00446 AC: 680 AN: 152316 Hom.: 6 Cov.: 32 AF XY: 0.00470 AC XY: 350 AN XY: 74482

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.00524

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00144 AC: 175

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;.;D
MetaRNN	Benign	0.0089	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N;N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.066	T;T;T;.;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.83	P;P;.;P;P
Vest4		0.70
MVP		0.46
MPC		0.50
ClinPred		0.042	T
GERP RS		4.4
Varity_R		0.66
gMVP		0.83

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: rs75208981; hg19: chr20-5935292;