10-13175546-C-T

Position:

• chr10-13175546-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018518.5(MCM10):​c.629C>T​(p.Pro210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM10	NM_018518.5	c.629C>T	p.Pro210Leu	missense_variant	6/20	ENST00000378714.8	NP_060988.3
MCM10	NM_182751.3	c.632C>T	p.Pro211Leu	missense_variant	6/20		NP_877428.1
MCM10	XM_011519538.3	c.632C>T	p.Pro211Leu	missense_variant	6/20		XP_011517840.1
MCM10	XM_047425437.1	c.629C>T	p.Pro210Leu	missense_variant	6/20		XP_047281393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM10	ENST00000378714.8	c.629C>T	p.Pro210Leu	missense_variant	6/20	1	NM_018518.5	ENSP00000367986.3
MCM10	ENST00000484800.6	c.632C>T	p.Pro211Leu	missense_variant	6/20	1		ENSP00000418268.1
MCM10	ENST00000378694.1	c.629C>T	p.Pro210Leu	missense_variant	5/18	5		ENSP00000367966.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251376 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2024

The c.632C>T (p.P211L) alteration is located in exon 6 (coding exon 5) of the MCM10 gene. This alteration results from a C to T substitution at nucleotide position 632, causing the proline (P) at amino acid position 211 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.23
DEOGEN2	Benign	0.089	.;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	.;L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.16
MutPred		0.19		.;Loss of glycosylation at P211 (P = 0.0268);.;
MVP		0.28
MPC		0.10
ClinPred		0.087	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs972437073; hg19: chr10-13217546;