2-135857243-C-G

Variant names:

• chr2-135857243-C-G
• rs309181
• NM_005915.6:c.1471-360G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005915.6(MCM6):​c.1471-360G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,958 control chromosomes in the GnomAD database, including 23,220 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (23220 hom., cov: 32)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.510
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM6	NM_005915.6	MANE Select	c.1471-360G>C		intron	N/A	NP_005906.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM6	ENST00000264156.3	TSL:1 MANE Select	c.1471-360G>C		intron	N/A	ENSP00000264156.2
	MCM6	ENST00000492091.1	TSL:5	n.181+5364G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76249 AN: 151840 Hom.: 23219 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.433

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.502 AC: 76266 AN: 151958 Hom.: 23220 Cov.: 32 AF XY: 0.493 AC XY: 36640 AN XY: 74282

African (AFR) AF: 0.220 AC: 9095 AN: 41430

American (AMR) AF: 0.392 AC: 5994 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3468

East Asian (EAS) AF: 0.358 AC: 1847 AN: 5156

South Asian (SAS) AF: 0.347 AC: 1670 AN: 4818

European-Finnish (FIN) AF: 0.698 AC: 7346 AN: 10526

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.701 AC: 47645 AN: 67972

Other (OTH) AF: 0.429 AC: 904 AN: 2108

Alfa AF: 0.455 Hom.: 1539

Bravo AF: 0.469

Asia WGS AF: 0.373 AC: 1295 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.57
DANN	Benign	0.58
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs309181; hg19: chr2-136614813;