rs2307340

chr22-35406668-C-Gchr22-35406668-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006739.4(MCM5):c.539C>G(p.Thr180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,611,746 control chromosomes in the GnomAD database, including 5,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.062 (385 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5120 hom.)
• Consequence: MCM5 NM_006739.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.169

Genes affected

MCM5 (HGNC:6948): (minichromosome maintenance complex component 5) The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018073916).
• BP6: Variant 22-35406668-C-G is Benign according to our data. Variant chr22-35406668-C-G is described in ClinVar as [Benign]. Clinvar id is 1674156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM5	NM_006739.4	c.539C>G	p.Thr180Ser	missense_variant	5/17	ENST00000216122.9
MCM5	XM_006724242.5	c.539C>G	p.Thr180Ser	missense_variant	5/18
MCM5	XM_047441366.1	c.539C>G	p.Thr180Ser	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM5	ENST00000216122.9	c.539C>G	p.Thr180Ser	missense_variant	5/17	1	NM_006739.4	P1

Frequencies

GnomAD3 genomes AF: 0.0615 AC: 9368 AN: 152206 Hom.: 385 Cov.: 32

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0864

Gnomad OTH AF: 0.0660

GnomAD3 exomes AF: 0.0633 AC: 15779 AN: 249334 Hom.: 693 AF XY: 0.0664 AC XY: 8960 AN XY: 134988

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.00288

Gnomad SAS exome AF: 0.0772

Gnomad FIN exome AF: 0.0948

Gnomad NFE exome AF: 0.0836

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0795 AC: 116059 AN: 1459422 Hom.: 5120 Cov.: 32 AF XY: 0.0799 AC XY: 58000 AN XY: 726150

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.0289

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.00438

Gnomad4 SAS exome AF: 0.0762

Gnomad4 FIN exome AF: 0.0946

Gnomad4 NFE exome AF: 0.0874

Gnomad4 OTH exome AF: 0.0717

GnomAD4 genome AF: 0.0615 AC: 9371 AN: 152324 Hom.: 385 Cov.: 32 AF XY: 0.0613 AC XY: 4562 AN XY: 74478

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.0763

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0864

Gnomad4 OTH AF: 0.0653

Alfa AF: 0.0677 Hom.: 293

Bravo AF: 0.0541

TwinsUK AF: 0.0847 AC: 314

ALSPAC AF: 0.0846 AC: 326

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.0855 AC: 735

ExAC AF: 0.0657 AC: 7971

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.0792

EpiControl AF: 0.0781

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MCM5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	14
Dann	Benign	0.87
DEOGEN2	Benign	0.043	T;T;.;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.42	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.0	N;.;.;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.75	T;T;T;T
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.082
MutPred		0.25		Gain of helix (P = 0.0425);.;.;.;
MPC		0.32
ClinPred		0.0010	T
GERP RS		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.036
gMVP		0.13

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: rs2307340; hg19: chr22-35802661; COSMIC: COSV53349065; COSMIC: COSV53349065;