2-135859184-C-T

Variant names:

• chr2-135859184-C-T
• rs182549
• NM_005915.6:c.1362+117G>A

Variant summary

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

The NM_005915.6(MCM6):​c.1362+117G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 819,600 control chromosomes in the GnomAD database, including 143,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.40 (17807 hom., cov: 32)
  • Exomes 𝑓: 0.56 (125432 hom.)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.140
• Publications: 100 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1362+117G>A		intron_variant	Intron 9 of 16	ENST00000264156.3	NP_005906.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM6	ENST00000264156.3	c.1362+117G>A		intron_variant	Intron 9 of 16	1	NM_005915.6	ENSP00000264156.2
MCM6	ENST00000492091.1	n.181+3423G>A		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes AF: 0.401 AC: 61022 AN: 152004 Hom.: 17812 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.641

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.557 AC: 371578 AN: 667478 Hom.: 125432 AF XY: 0.540 AC XY: 185644 AN XY: 343926

African (AFR) AF: 0.102 AC: 1638 AN: 16002

American (AMR) AF: 0.198 AC: 4006 AN: 20202

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 1935 AN: 15046

East Asian (EAS) AF: 0.000582 AC: 18 AN: 30920

South Asian (SAS) AF: 0.232 AC: 11281 AN: 48604

European-Finnish (FIN) AF: 0.595 AC: 19955 AN: 33534

Middle Eastern (MID) AF: 0.0558 AC: 131 AN: 2348

European-Non Finnish (NFE) AF: 0.677 AC: 317120 AN: 468242

Other (OTH) AF: 0.476 AC: 15494 AN: 32580

GnomAD4 genome AF: 0.401 AC: 61009 AN: 152122 Hom.: 17807 Cov.: 32 AF XY: 0.385 AC XY: 28658 AN XY: 74366

African (AFR) AF: 0.122 AC: 5075 AN: 41506

American (AMR) AF: 0.231 AC: 3531 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 463 AN: 3464

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5172

South Asian (SAS) AF: 0.179 AC: 865 AN: 4832

European-Finnish (FIN) AF: 0.579 AC: 6117 AN: 10560

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.641 AC: 43601 AN: 67990

Other (OTH) AF: 0.297 AC: 627 AN: 2110

Alfa AF: 0.512 Hom.: 31789

Bravo AF: 0.363

Asia WGS AF: 0.0780 AC: 274 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

LACTASE PERSISTENCE Other:1

Jan 26, 2021

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.68
DANN	Benign	0.34
PhyloP100		0.14
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: rs182549; hg19: chr2-136616754;