3-127599515-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004526.4(MCM2):c.204T>G(p.Asp68Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,972 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: MCM2 NM_004526.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.450

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003677994).
• BP6: Variant 3-127599515-T-G is Benign according to our data. Variant chr3-127599515-T-G is described in ClinVar as [Benign]. Clinvar id is 678700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1915/152248) while in subpopulation AFR AF= 0.0427 (1773/41546). AF 95% confidence interval is 0.041. There are 35 homozygotes in gnomad4. There are 874 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1914 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM2	NM_004526.4	c.204T>G	p.Asp68Glu	missense_variant	2/16	ENST00000265056.12
MCM2	XM_024453531.2	c.177T>G	p.Asp59Glu	missense_variant	2/16
MCM2	NR_073375.2	n.260T>G		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM2	ENST00000265056.12	c.204T>G	p.Asp68Glu	missense_variant	2/16	1	NM_004526.4	P1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1914 AN: 152130 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00328 AC: 824 AN: 251094 Hom.: 15 AF XY: 0.00227 AC XY: 308 AN XY: 135736

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00134 AC: 1958 AN: 1461724 Hom.: 33 Cov.: 30 AF XY: 0.00113 AC XY: 825 AN XY: 727154

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.0126 AC: 1915 AN: 152248 Hom.: 35 Cov.: 33 AF XY: 0.0117 AC XY: 874 AN XY: 74442

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00291 Hom.: 7

Bravo AF: 0.0142

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00408 AC: 495

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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

Jul 12, 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	0.076
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.028	T;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.12	N;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.54	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.15
MutPred		0.094		Gain of helix (P = 0.1736);.;.;
MVP		0.35
MPC		0.37
ClinPred		0.0098	T
GERP RS		2.8
Varity_R		0.18
gMVP		0.064

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: rs3087452; hg19: chr3-127318358;