NM_001256378.2:c.1217G>T

Variant names:

• chr10-119840868-C-A
• rs558629876
• NM_001256378.2:c.1217G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256378.2(MCMBP):​c.1217G>T​(p.Arg406Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,448,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R406Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MCMBP NM_001256378.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 0 publications found

Genes affected

MCMBP (HGNC:25782): (minichromosome maintenance complex binding protein) This gene encodes a protein which is a component of the hexameric minichromosome maintenance (MCM) complex which regulates initiation and elongation of DNA. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40294984).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256378.2. 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
	MCMBP	NM_001256378.2	MANE Select	c.1217G>T	p.Arg406Leu	missense	Exon 11 of 16	NP_001243307.1	A0A0S2Z5P5
	MCMBP	NM_024834.4		c.1223G>T	p.Arg408Leu	missense	Exon 11 of 16	NP_079110.1	Q9BTE3-1
	MCMBP	NM_001256379.2		c.698G>T	p.Arg233Leu	missense	Exon 11 of 16	NP_001243308.1	Q9BTE3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCMBP	ENST00000369077.4	TSL:1 MANE Select	c.1217G>T	p.Arg406Leu	missense	Exon 11 of 16	ENSP00000358073.3	Q9BTE3-2
	MCMBP	ENST00000360003.7	TSL:2	c.1223G>T	p.Arg408Leu	missense	Exon 11 of 16	ENSP00000353098.3	Q9BTE3-1
	MCMBP	ENST00000966480.1		c.1223G>T	p.Arg408Leu	missense	Exon 11 of 16	ENSP00000636539.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1448400 Hom.: 0 Cov.: 29 AF XY: 0.00000695 AC XY: 5 AN XY: 719840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 42324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.00 AC: 0 AN: 81860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1106776

Other (OTH) AF: 0.00 AC: 0 AN: 59976

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00354970), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.047
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.36	B
Vest4		0.69
MutPred		0.49		Gain of catalytic residue at Q411 (P = 0.1115)
MVP		0.043
MPC		0.37
ClinPred		0.86	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.56
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs558629876; hg19: chr10-121600380;