NM_005915.6:c.2268C>T

Variant names:

• chr2-135844626-G-A
• rs4988270
• NM_005915.6:c.2268C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005915.6(MCM6):​c.2268C>T​(p.Ile756Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,585,624 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (23 hom.)
• Consequence: MCM6 NM_005915.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.955
• Publications: 7 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-135844626-G-A is Benign according to our data. Variant chr2-135844626-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 781948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.955 with no splicing effect.
• BS2: High AC in GnomAd4 at 517 AD gene.

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.2268C>T	p.Ile756Ile	synonymous	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.2268C>T	p.Ile756Ile	synonymous	Exon 16 of 17	ENSP00000264156.2	Q14566
	MCM6	ENST00000884967.1		c.2265C>T	p.Ile755Ile	synonymous	Exon 16 of 17	ENSP00000555026.1
	MCM6	ENST00000939153.1		c.2265C>T	p.Ile755Ile	synonymous	Exon 16 of 17	ENSP00000609212.1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 517 AN: 151818 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00313

Gnomad FIN AF: 0.00997

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00382 AC: 888 AN: 232360 AF XY: 0.00423

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.0000598

Gnomad FIN exome AF: 0.00798

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00349 AC: 5006 AN: 1433688 Hom.: 23 Cov.: 31 AF XY: 0.00370 AC XY: 2634 AN XY: 712058

African (AFR) AF: 0.000432 AC: 14 AN: 32400

American (AMR) AF: 0.00117 AC: 47 AN: 40068

Ashkenazi Jewish (ASJ) AF: 0.00964 AC: 248 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 38230

South Asian (SAS) AF: 0.00281 AC: 223 AN: 79356

European-Finnish (FIN) AF: 0.00823 AC: 433 AN: 52636

Middle Eastern (MID) AF: 0.00245 AC: 14 AN: 5714

European-Non Finnish (NFE) AF: 0.00347 AC: 3823 AN: 1100170

Other (OTH) AF: 0.00344 AC: 204 AN: 59384

GnomAD4 genome AF: 0.00340 AC: 517 AN: 151936 Hom.: 4 Cov.: 31 AF XY: 0.00330 AC XY: 245 AN XY: 74232

African (AFR) AF: 0.000338 AC: 14 AN: 41422

American (AMR) AF: 0.00164 AC: 25 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 40 AN: 3462

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00313 AC: 15 AN: 4792

European-Finnish (FIN) AF: 0.00997 AC: 105 AN: 10534

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00449 AC: 305 AN: 67994

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00407 Hom.: 2

Bravo AF: 0.00250

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		-0.95
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4988270; hg19: chr2-136602196;