2-135844558-C-G

Variant names:

• chr2-135844558-C-G
• rs770990427
• NM_005915.6:c.2336G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005915.6(MCM6):​c.2336G>C​(p.Arg779Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R779Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MCM6 NM_005915.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

Genes affected

MCM6 (HGNC:6949): (minichromosome maintenance complex component 6) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of the complex by CDC2 kinase reduces the helicase activity, suggesting a role in the regulation of DNA replication. Single nucleotide polymorphisms in the intron regions of this gene are associated with differential transcriptional activation of the promoter of the neighboring lactase gene and, thereby, influence lactose intolerance in early adulthood. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005915.6. 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
	MCM6	NM_005915.6	MANE Select	c.2336G>C	p.Arg779Pro	missense	Exon 16 of 17	NP_005906.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM6	ENST00000264156.3	TSL:1 MANE Select	c.2336G>C	p.Arg779Pro	missense	Exon 16 of 17	ENSP00000264156.2	Q14566
	MCM6	ENST00000884967.1		c.2333G>C	p.Arg778Pro	missense	Exon 16 of 17	ENSP00000555026.1
	MCM6	ENST00000939153.1		c.2333G>C	p.Arg778Pro	missense	Exon 16 of 17	ENSP00000609212.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417992 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703250

African (AFR) AF: 0.00 AC: 0 AN: 31782

American (AMR) AF: 0.00 AC: 0 AN: 38166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24986

East Asian (EAS) AF: 0.00 AC: 0 AN: 37624

South Asian (SAS) AF: 0.00 AC: 0 AN: 76200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092618

Other (OTH) AF: 0.00 AC: 0 AN: 58724

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.69		Loss of MoRF binding (P = 0.0074)
MVP		0.75
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.92
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs770990427; hg19: chr2-136602128;