20-5952004-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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

GnomAD3 exomes AF: 0.0264 AC: 6486 AN: 245514 Hom.: 190 AF XY: 0.0233 AC XY: 3100 AN XY: 132850

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 SAS exome AF: 0.00457

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

Gnomad4 AFR exome AF: 0.00382

Gnomad4 AMR exome AF: 0.0859

Gnomad4 ASJ exome AF: 0.00801

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00525

Gnomad4 FIN exome AF: 0.0509

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0198

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

Gnomad4 AFR AF: 0.00530

Gnomad4 AMR AF: 0.0504

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00478

Gnomad4 FIN AF: 0.0479

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0195

Alfa AF: 0.0218 Hom.: 49

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17220251; hg19: chr20-5932650;