10-13175636-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018518.5(MCM10):c.719C>T(p.Thr240Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,204 control chromosomes in the GnomAD database, including 8 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (6 hom.)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07

Genes affected

MCM10 (HGNC:18043): (minichromosome maintenance 10 replication initiation factor) 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 it may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein can interact with MCM2 and MCM6, as well as with the origin recognition protein ORC2. It is regulated by proteolysis and phosphorylation in a cell cycle-dependent manner. Studies of a similar protein in Xenopus suggest that the chromatin binding of this protein at the onset of DNA replication is after pre-RC assembly and before origin unwinding. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052666366).
• BP6: Variant 10-13175636-C-T is Benign according to our data. Variant chr10-13175636-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2640310.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM10	NM_018518.5	c.719C>T	p.Thr240Met	missense_variant	6/20	ENST00000378714.8
MCM10	NM_182751.3	c.722C>T	p.Thr241Met	missense_variant	6/20
MCM10	XM_011519538.3	c.722C>T	p.Thr241Met	missense_variant	6/20
MCM10	XM_047425437.1	c.719C>T	p.Thr240Met	missense_variant	6/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM10	ENST00000378714.8	c.719C>T	p.Thr240Met	missense_variant	6/20	1	NM_018518.5	P4
MCM10	ENST00000484800.6	c.722C>T	p.Thr241Met	missense_variant	6/20	1		A1
MCM10	ENST00000378694.1	c.719C>T	p.Thr240Met	missense_variant	5/18	5

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00705

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00181 AC: 453 AN: 250896 Hom.: 2 AF XY: 0.00159 AC XY: 216 AN XY: 135578

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00102 AC: 1496 AN: 1460924 Hom.: 6 Cov.: 30 AF XY: 0.00100 AC XY: 728 AN XY: 726782

Gnomad4 AFR exome AF: 0.00693

Gnomad4 AMR exome AF: 0.00486

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000708

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74456

Gnomad4 AFR AF: 0.00703

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00424

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00184

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

MCM10: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.32
Dann	Benign	0.78
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.26	B;B;B
Vest4		0.11
MVP		0.19
MPC		0.11
ClinPred		0.0012	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.0081
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35586085; hg19: chr10-13217636; COSMIC: COSV66333678; COSMIC: COSV66333678;