chr6-52267932-C-T

Variant names:

• chr6-52267932-C-T
• rs2128275630
• NM_002388.6:c.2005G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002388.6(MCM3):​c.2005G>A​(p.Glu669Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCM3 NM_002388.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15248835).

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.2005G>A	p.Glu669Lys	missense	Exon 14 of 17	NP_002379.4
	MCM3	NM_001366369.2		c.2005G>A	p.Glu669Lys	missense	Exon 14 of 18	NP_001353298.1	A0A0S2Z492
	MCM3	NM_001366370.2		c.2056G>A	p.Glu686Lys	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.2005G>A	p.Glu669Lys	missense	Exon 14 of 17	ENSP00000472940.2	P25205-1
	MCM3	ENST00000616552.4	TSL:1	c.2140G>A	p.Glu714Lys	missense	Exon 14 of 17	ENSP00000480987.1	P25205-2
	MCM3	ENST00000229854.12	TSL:1	c.2035G>A	p.Glu679Lys	missense	Exon 13 of 16	ENSP00000229854.6	A0A499FHX9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432102 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 714428

African (AFR) AF: 0.00 AC: 0 AN: 32886

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085142

Other (OTH) AF: 0.00 AC: 0 AN: 59384

GnomAD4 genome Cov.: 31

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	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.11
Sift	Benign	0.44	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.42		Gain of MoRF binding (P = 0.0229)
MVP		0.44
MPC		0.22
ClinPred		0.50	T
GERP RS		4.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.15
gMVP		0.24
Mutation Taster		=89/11	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: rs2128275630; hg19: chr6-52132730;