22-35406668-C-G

Variant names:

• chr22-35406668-C-G
• rs2307340
• NM_006739.4:c.539C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: -0.169
• Publications: 24 publications found

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]

MCM5 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 8

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006739.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM5	NM_006739.4	MANE Select	c.539C>G	p.Thr180Ser	missense	Exon 5 of 17	NP_006730.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM5	ENST00000216122.9	TSL:1 MANE Select	c.539C>G	p.Thr180Ser	missense	Exon 5 of 17	ENSP00000216122.3	P33992
	MCM5	ENST00000917548.1		c.539C>G	p.Thr180Ser	missense	Exon 5 of 17	ENSP00000587607.1
	MCM5	ENST00000917543.1		c.539C>G	p.Thr180Ser	missense	Exon 5 of 18	ENSP00000587602.1

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

GnomAD2 exomes AF: 0.0633 AC: 15779 AN: 249334 AF XY: 0.0664

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 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

African (AFR) AF: 0.0224 AC: 750 AN: 33478

American (AMR) AF: 0.0289 AC: 1292 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 679 AN: 26132

East Asian (EAS) AF: 0.00438 AC: 174 AN: 39700

South Asian (SAS) AF: 0.0762 AC: 6576 AN: 86250

European-Finnish (FIN) AF: 0.0946 AC: 4835 AN: 51116

Middle Eastern (MID) AF: 0.0413 AC: 238 AN: 5758

European-Non Finnish (NFE) AF: 0.0874 AC: 97188 AN: 1111900

Other (OTH) AF: 0.0717 AC: 4327 AN: 60366

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

African (AFR) AF: 0.0268 AC: 1115 AN: 41588

American (AMR) AF: 0.0433 AC: 662 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.00482 AC: 25 AN: 5182

South Asian (SAS) AF: 0.0763 AC: 368 AN: 4826

European-Finnish (FIN) AF: 0.101 AC: 1077 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0864 AC: 5878 AN: 68026

Other (OTH) AF: 0.0653 AC: 138 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MCM5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.17
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.093
Sift	Benign	0.75	T
Sift4G	Benign	0.75	T
Polyphen		0.0	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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