3-127598471-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_004526.4(MCM2):c.5C>A(p.Ala2Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000992 in 1,612,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MCM2
NM_004526.4 missense, splice_region

Scores

Splicing: ADA: 0.2448

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Variant links:

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]

MCM2 links:

TPRA1 (HGNC:30413): (transmembrane protein adipocyte associated 1) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Predicted to act upstream of or within embryonic cleavage and negative regulation of mitotic cell cycle phase transition. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TPRA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity MCM2_HUMAN

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM2	NM_004526.4 link	c.5C>A	p.Ala2Glu	missense_variant, splice_region_variant	Exon 1 of 16	ENST00000265056.12	NP_004517.2	P49736

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCM2	ENST00000265056.12 link	c.5C>A	p.Ala2Glu	missense_variant, splice_region_variant	Exon 1 of 16	1	NM_004526.4	ENSP00000265056.7	P49736
MCM2	ENST00000474964.5 link	n.5C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 16	2		ENSP00000420007.1	F8WDM3
TPRA1	ENST00000648957.1 link	c.-1062G>T		upstream_gene_variant				ENSP00000498161.1	Q86W33-1
TPRA1	ENST00000490643.5 link	c.-488G>T		upstream_gene_variant		5		ENSP00000419822.1	C9JZ00

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

247152

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134084

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460604

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2 of the MCM2 protein (p.Ala2Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MCM2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.54

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.51

REVEL

Benign

0.17

Sift

Uncertain

0.0070

Sift4G

Benign

0.53

Polyphen

1.0

Vest4

0.51

MutPred

0.18

Loss of catalytic residue at M1 (P = 0.0231);

MVP

0.36

MPC

0.95

ClinPred

0.73

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.24

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over