3-127599326-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004526.4(MCM2):c.15G>A(p.Ser5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,614,060 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: MCM2 NM_004526.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.81

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-127599326-G-A is Benign according to our data. Variant chr3-127599326-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1316005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.81 with no splicing effect.
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM2	NM_004526.4	c.15G>A	p.Ser5=	synonymous_variant	2/16	ENST00000265056.12
MCM2	XM_024453531.2	c.-13G>A		5_prime_UTR_variant	2/16
MCM2	NR_073375.2	n.71G>A		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM2	ENST00000265056.12	c.15G>A	p.Ser5=	synonymous_variant	2/16	1	NM_004526.4	P1
MCM2	ENST00000472731.1	c.-13G>A		5_prime_UTR_variant	1/2	2
MCM2	ENST00000480910.1	c.-13G>A		5_prime_UTR_variant	2/3	2
MCM2	ENST00000474964.5	c.15G>A	p.Ser5=	synonymous_variant, NMD_transcript_variant	2/16	2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251148 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135746

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

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: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000350 AC: 511 AN: 1461732 Hom.: 1 Cov.: 30 AF XY: 0.000315 AC XY: 229 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

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: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000294 Hom.: 1

Bravo AF: 0.000189

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	4.8
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs148166817; hg19: chr3-127318169;