rs3087450

Positions:

• chr3-127608466-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004526.4(MCM2):​c.1186G>A​(p.Ala396Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0107 in 1,614,204 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0083 (15 hom., cov: 32)
  • Exomes 𝑓: 0.011 (106 hom.)
• Consequence: MCM2 NM_004526.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.17

Genes affected

MCM2 (HGNC:6944): (minichromosome maintenance complex component 2) 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 forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008700162).
• BP6: Variant 3-127608466-G-A is Benign according to our data. Variant chr3-127608466-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 508564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1266 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM2	NM_004526.4	c.1186G>A	p.Ala396Thr	missense_variant	7/16	ENST00000265056.12
MCM2	XM_024453531.2	c.1159G>A	p.Ala387Thr	missense_variant	7/16
MCM2	NR_073375.2	n.1261G>A		non_coding_transcript_exon_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM2	ENST00000265056.12	c.1186G>A	p.Ala396Thr	missense_variant	7/16	1	NM_004526.4	P1
MCM2	ENST00000491422.1	c.775G>A	p.Ala259Thr	missense_variant	4/14	5
MCM2	ENST00000474964.5	c.*764G>A		3_prime_UTR_variant, NMD_transcript_variant	7/16	2
MCM2	ENST00000477668.5	c.*764G>A		3_prime_UTR_variant, NMD_transcript_variant	6/14	2

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152224 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00804 AC: 2020 AN: 251380 Hom.: 9 AF XY: 0.00829 AC XY: 1126 AN XY: 135878

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.0110 AC: 16025 AN: 1461862 Hom.: 106 Cov.: 31 AF XY: 0.0109 AC XY: 7931 AN XY: 727230

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.0304

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00356

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00831 AC: 1266 AN: 152342 Hom.: 15 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74488

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0120 Hom.: 27

Bravo AF: 0.00832

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00805 AC: 978

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MCM2: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MCM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.52	P
Vest4		0.76
MVP		0.46
MPC		0.37
ClinPred		0.0082	T
GERP RS		5.3
Varity_R		0.51
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs3087450; hg19: chr3-127327309; COSMIC: COSV99413668; COSMIC: COSV99413668;