chr6-52267871-C-T

Variant names:

• chr6-52267871-C-T
• rs772036028
• NM_002388.6:c.2066G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002388.6(MCM3):​c.2066G>A​(p.Arg689Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,122,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MCM3 NM_002388.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.626
• Publications: 0 publications found

Genes affected

MCM3 (HGNC:6945): (minichromosome maintenance complex component 3) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein is a subunit of the protein complex that consists of MCM2-7. It has been shown to interact directly with MCM5/CDC46. This protein also interacts with and is acetylated by MCM3AP, a chromatin-associated acetyltransferase. The acetylation of this protein inhibits the initiation of DNA replication and cell cycle progression. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2018]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052104443).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002388.6. 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
	MCM3	NM_002388.6	MANE Select	c.2066G>A	p.Arg689Lys	missense	Exon 14 of 17	NP_002379.4
	MCM3	NM_001366369.2		c.2066G>A	p.Arg689Lys	missense	Exon 14 of 18	NP_001353298.1	A0A0S2Z492
	MCM3	NM_001366370.2		c.2117G>A	p.Arg706Lys	missense	Exon 14 of 17	NP_001353299.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3	ENST00000596288.7	TSL:1 MANE Select	c.2066G>A	p.Arg689Lys	missense	Exon 14 of 17	ENSP00000472940.2	P25205-1
	MCM3	ENST00000616552.4	TSL:1	c.2201G>A	p.Arg734Lys	missense	Exon 14 of 17	ENSP00000480987.1	P25205-2
	MCM3	ENST00000229854.12	TSL:1	c.2096G>A	p.Arg699Lys	missense	Exon 13 of 16	ENSP00000229854.6	A0A499FHX9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000541 AC: 1 AN: 184706 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 6 AN: 970654 Hom.: 0 Cov.: 13 AF XY: 0.00000800 AC XY: 4 AN XY: 499860

African (AFR) AF: 0.00 AC: 0 AN: 23544

American (AMR) AF: 0.00 AC: 0 AN: 37128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22554

East Asian (EAS) AF: 0.00 AC: 0 AN: 34816

South Asian (SAS) AF: 0.00 AC: 0 AN: 72570

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 50904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4842

European-Non Finnish (NFE) AF: 0.00000588 AC: 4 AN: 680422

Other (OTH) AF: 0.0000228 AC: 1 AN: 43874

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000836 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
PhyloP100		-0.63
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.10
Sift	Benign	0.60	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.24		Gain of methylation at R689 (P = 0.0186)
MVP		0.28
MPC		0.19
ClinPred		0.55	D
GERP RS		0.23
Varity_R		0.035
gMVP		0.14
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772036028; hg19: chr6-52132669;