10-13171215-C-G

Variant names:

• chr10-13171215-C-G
• rs373953435
• NM_018518.5:c.301C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018518.5(MCM10):​c.301C>G​(p.Leu101Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L101F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM10 NM_018518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 1 publications found

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]

MCM10 Gene-Disease associations (from GenCC):

• immunodeficiency 80 with or without congenital cardiomyopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04886651).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018518.5. 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
	MCM10	NM_018518.5	MANE Select	c.301C>G	p.Leu101Val	missense	Exon 3 of 20	NP_060988.3
	MCM10	NM_182751.3		c.301C>G	p.Leu101Val	missense	Exon 3 of 20	NP_877428.1	Q7L590-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM10	ENST00000378714.8	TSL:1 MANE Select	c.301C>G	p.Leu101Val	missense	Exon 3 of 20	ENSP00000367986.3	Q7L590-2
	MCM10	ENST00000484800.6	TSL:1	c.301C>G	p.Leu101Val	missense	Exon 3 of 20	ENSP00000418268.1	Q7L590-1
	MCM10	ENST00000921435.1		c.301C>G	p.Leu101Val	missense	Exon 3 of 20	ENSP00000591494.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250604 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.35
DANN	Benign	0.57
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.37
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.0090
Sift	Benign	0.26	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.036
MutPred		0.043		Loss of glycosylation at P104 (P = 0.1336)
MVP		0.15
MPC		0.10
ClinPred		0.046	T
GERP RS		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.043
Mutation Taster		=92/8	polymorphism

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: rs373953435; hg19: chr10-13213215;