10-13175530-A-G

Variant names:

• chr10-13175530-A-G
• NM_018518.5:c.613A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018518.5(MCM10):​c.613A>G​(p.Arg205Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.194

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04370874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM10	NM_018518.5	c.613A>G	p.Arg205Gly	missense_variant	Exon 6 of 20	ENST00000378714.8	NP_060988.3
MCM10	NM_182751.3	c.616A>G	p.Arg206Gly	missense_variant	Exon 6 of 20		NP_877428.1
MCM10	XM_011519538.3	c.616A>G	p.Arg206Gly	missense_variant	Exon 6 of 20		XP_011517840.1
MCM10	XM_047425437.1	c.613A>G	p.Arg205Gly	missense_variant	Exon 6 of 20		XP_047281393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM10	ENST00000378714.8	c.613A>G	p.Arg205Gly	missense_variant	Exon 6 of 20	1	NM_018518.5	ENSP00000367986.3
MCM10	ENST00000484800.6	c.616A>G	p.Arg206Gly	missense_variant	Exon 6 of 20	1		ENSP00000418268.1
MCM10	ENST00000378694.1	c.613A>G	p.Arg205Gly	missense_variant	Exon 5 of 18	5		ENSP00000367966.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.616A>G (p.R206G) alteration is located in exon 6 (coding exon 5) of the MCM10 gene. This alteration results from a A to G substitution at nucleotide position 616, causing the arginine (R) at amino acid position 206 to be replaced by a glycine (G). 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	0.069
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.090	.;T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.072
MutPred		0.23		.;Loss of stability (P = 0.015);.;
MVP		0.18
MPC		0.13
ClinPred		0.028	T
GERP RS		-0.82
Varity_R		0.061
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-13217530;