20-5955186-A-G

Variant names:

• chr20-5955186-A-G
• rs116926921
• NM_032485.6:c.421A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032485.6(MCM8):​c.421A>G​(p.Ile141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,964 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (15 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.105
• Publications: 3 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: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.0047038198).
• BP6: Variant 20-5955186-A-G is Benign according to our data. Variant chr20-5955186-A-G is described in ClinVar as Benign. ClinVar VariationId is 708742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00128 (195/152356) while in subpopulation EAS AF = 0.00791 (41/5186). AF 95% confidence interval is 0.00599. There are 1 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032485.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	NM_032485.6	MANE Select	c.421A>G	p.Ile141Val	missense	Exon 5 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.421A>G	p.Ile141Val	missense	Exon 5 of 19	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.421A>G	p.Ile141Val	missense	Exon 5 of 19	NP_001268449.1	Q9UJA3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	ENST00000610722.4	TSL:1 MANE Select	c.421A>G	p.Ile141Val	missense	Exon 5 of 19	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.421A>G	p.Ile141Val	missense	Exon 5 of 24	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.421A>G	p.Ile141Val	missense	Exon 5 of 19	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00220 AC: 553 AN: 251286 AF XY: 0.00250

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00139 AC: 2025 AN: 1461608 Hom.: 15 Cov.: 31 AF XY: 0.00151 AC XY: 1100 AN XY: 727108

African (AFR) AF: 0.000807 AC: 27 AN: 33472

American (AMR) AF: 0.000805 AC: 36 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26124

East Asian (EAS) AF: 0.00716 AC: 284 AN: 39664

South Asian (SAS) AF: 0.00622 AC: 536 AN: 86202

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53414

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.000741 AC: 824 AN: 1111868

Other (OTH) AF: 0.00260 AC: 157 AN: 60384

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74506

African (AFR) AF: 0.000289 AC: 12 AN: 41584

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5186

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00164 Hom.: 2

Bravo AF: 0.00110

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.10
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.036
Sift	Benign	0.17	T
Sift4G	Uncertain	0.057	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.15
MPC		0.11
ClinPred		0.0020	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.47
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs116926921; hg19: chr20-5935832;