chr3-127598471-C-A
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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
NM_004526.4 missense, splice_region
Scores
6
13
Splicing: ADA: 0.2448
2
Clinical Significance
Conservation
PhyloP100: 4.15
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]
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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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCM2 | NM_004526.4 | c.5C>A | p.Ala2Glu | missense_variant, splice_region_variant | 1/16 | ENST00000265056.12 | |
MCM2 | NR_073375.2 | n.61C>A | splice_region_variant, non_coding_transcript_exon_variant | 1/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCM2 | ENST00000265056.12 | c.5C>A | p.Ala2Glu | missense_variant, splice_region_variant | 1/16 | 1 | NM_004526.4 | P1 | |
MCM2 | ENST00000474964.5 | c.5C>A | p.Ala2Glu | missense_variant, splice_region_variant, NMD_transcript_variant | 1/16 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247152Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134084
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GnomAD4 exome AF: 0.00000959 AC: 14AN: 1460604Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 726642
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | 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. 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"). This variant has not been reported in the literature in individuals affected with MCM2-related conditions. 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 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.0231);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at