20-5952004-C-T

Variant names:

• chr20-5952004-C-T
• rs17220251
• NM_032485.6:c.-5-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032485.6(MCM8):​c.-5-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,606,112 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (52 hom., cov: 32)
  • Exomes 𝑓: 0.021 (496 hom.)
• Consequence: MCM8 NM_032485.6 splice_region, intron
• Scores: Splicing: ADA: 0.00006245
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.606
• Publications: 5 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]

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

ENSG00000286235 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-5952004-C-T is Benign according to our data. Variant chr20-5952004-C-T is described in ClinVar as [Benign]. Clinvar id is 1270703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6	c.-5-7C>T		splice_region_variant, intron_variant	Intron 1 of 18	ENST00000610722.4	NP_115874.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4	c.-5-7C>T		splice_region_variant, intron_variant	Intron 1 of 18	1	NM_032485.6	ENSP00000478141.1
ENSG00000286235	ENST00000652720.1	c.-5-7C>T		splice_region_variant, intron_variant	Intron 1 of 23			ENSP00000498784.1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2893 AN: 151966 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00532

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0202

GnomAD2 exomes AF: 0.0264 AC: 6486 AN: 245514 AF XY: 0.0233

Gnomad AFR exome AF: 0.00475

Gnomad AMR exome AF: 0.0891

Gnomad ASJ exome AF: 0.00795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0494

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0232

GnomAD4 exome AF: 0.0211 AC: 30624 AN: 1454028 Hom.: 496 Cov.: 30 AF XY: 0.0203 AC XY: 14684 AN XY: 723410

African (AFR) AF: 0.00382 AC: 126 AN: 33010

American (AMR) AF: 0.0859 AC: 3677 AN: 42792

Ashkenazi Jewish (ASJ) AF: 0.00801 AC: 207 AN: 25858

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39618

South Asian (SAS) AF: 0.00525 AC: 447 AN: 85148

European-Finnish (FIN) AF: 0.0509 AC: 2711 AN: 53230

Middle Eastern (MID) AF: 0.00542 AC: 31 AN: 5718

European-Non Finnish (NFE) AF: 0.0201 AC: 22235 AN: 1108604

Other (OTH) AF: 0.0198 AC: 1188 AN: 60050

GnomAD4 genome AF: 0.0191 AC: 2904 AN: 152084 Hom.: 52 Cov.: 32 AF XY: 0.0200 AC XY: 1489 AN XY: 74320

African (AFR) AF: 0.00530 AC: 220 AN: 41476

American (AMR) AF: 0.0504 AC: 770 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00478 AC: 23 AN: 4810

European-Finnish (FIN) AF: 0.0479 AC: 506 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0191 AC: 1298 AN: 67994

Other (OTH) AF: 0.0195 AC: 41 AN: 2102

Alfa AF: 0.0194 Hom.: 119

Bravo AF: 0.0204

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32155011) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.65
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0
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: rs17220251; hg19: chr20-5932650;