rs309180

Variant names:

• chr2-135856685-G-A
• rs309180
• NM_005915.6:c.1626+43C>T

Variant summary

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

The NM_005915.6(MCM6):​c.1626+43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,597,080 control chromosomes in the GnomAD database, including 380,785 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 (23211 hom., cov: 30)
  • Exomes 𝑓: 0.68 (357574 hom.)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118
• Publications: 25 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1626+43C>T		intron_variant	Intron 11 of 16	ENST00000264156.3	NP_005906.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM6	ENST00000264156.3	c.1626+43C>T		intron_variant	Intron 11 of 16	1	NM_005915.6	ENSP00000264156.2
MCM6	ENST00000492091.1	n.182-5122C>T		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76170 AN: 151798 Hom.: 23210 Cov.: 30

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.538 AC: 129126 AN: 240140 AF XY: 0.539

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.370

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.689

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.679 AC: 981829 AN: 1445164 Hom.: 357574 Cov.: 26 AF XY: 0.667 AC XY: 479604 AN XY: 718606

African (AFR) AF: 0.192 AC: 6314 AN: 32938

American (AMR) AF: 0.408 AC: 17695 AN: 43418

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7122 AN: 25208

East Asian (EAS) AF: 0.384 AC: 15183 AN: 39588

South Asian (SAS) AF: 0.383 AC: 32051 AN: 83732

European-Finnish (FIN) AF: 0.695 AC: 36605 AN: 52704

Middle Eastern (MID) AF: 0.223 AC: 1249 AN: 5594

European-Non Finnish (NFE) AF: 0.753 AC: 829534 AN: 1102240

Other (OTH) AF: 0.604 AC: 36076 AN: 59742

GnomAD4 genome AF: 0.501 AC: 76184 AN: 151916 Hom.: 23211 Cov.: 30 AF XY: 0.493 AC XY: 36583 AN XY: 74224

African (AFR) AF: 0.218 AC: 9041 AN: 41428

American (AMR) AF: 0.392 AC: 5977 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 993 AN: 3462

East Asian (EAS) AF: 0.359 AC: 1852 AN: 5160

South Asian (SAS) AF: 0.347 AC: 1668 AN: 4806

European-Finnish (FIN) AF: 0.698 AC: 7354 AN: 10542

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

European-Non Finnish (NFE) AF: 0.701 AC: 47625 AN: 67958

Other (OTH) AF: 0.428 AC: 901 AN: 2106

Alfa AF: 0.587 Hom.: 18949

Bravo AF: 0.468

Asia WGS AF: 0.370 AC: 1288 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.63
PhyloP100		0.12
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: rs309180; hg19: chr2-136614255; COSMIC: COSV51466697; COSMIC: COSV51466697;