Genetic Variant MCM6:c.1756-187C>T (chr2-135851750-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005915.6(MCM6):c.1756-187C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 423,448 control chromosomes in the GnomAD database, including 849 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 0.063 ( 573 hom., cov: 32)

Exomes 𝑓: 0.033 ( 276 hom. )

Consequence

MCM6
NM_005915.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.650

Publications

3 publications found

Variant links:

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]

MCM6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM6	NM_005915.6 link	c.1756-187C>T		intron_variant	Intron 12 of 16	ENST00000264156.3	NP_005906.2	Q14566

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCM6	ENST00000264156.3 link	c.1756-187C>T	intron_variant	Intron 12 of 16	1	NM_005915.6	ENSP00000264156.2	Q14566
MCM6	ENST00000483902.1 link	n.196C>T	non_coding_transcript_exon_variant	Exon 1 of 2	2
MCM6	ENST00000492091.1 link	n.182-187C>T	intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0628

AC:

9546

AN:

152110

Hom.:

576

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0400

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.0599

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.0231

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0507

GnomAD4 exome

AF:

0.0333

AC:

9043

AN:

271220

Hom.:

276

Cov.:

AF XY:

0.0331

AC XY:

4577

AN XY:

138300

show subpopulations

African (AFR)

AF:

0.151

AC:

1370

AN:

9096

American (AMR)

AF:

0.0349

AC:

360

AN:

10304

Ashkenazi Jewish (ASJ)

AF:

0.0531

AC:

504

AN:

9490

East Asian (EAS)

AF:

0.0548

AC:

1326

AN:

24202

South Asian (SAS)

AF:

0.0154

AC:

112

AN:

7268

European-Finnish (FIN)

AF:

0.0249

AC:

473

AN:

18966

Middle Eastern (MID)

AF:

0.0453

AC:

AN:

1302

European-Non Finnish (NFE)

AF:

0.0239

AC:

4151

AN:

173630

Other (OTH)

AF:

0.0406

AC:

688

AN:

16962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

394

788

1183

1577

1971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0628

AC:

9554

AN:

152228

Hom.:

573

Cov.:

AF XY:

0.0608

AC XY:

4525

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.155

AC:

6416

AN:

41512

American (AMR)

AF:

0.0402

AC:

615

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.0602

AC:

312

AN:

5184

South Asian (SAS)

AF:

0.0180

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0231

AC:

245

AN:

10610

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1578

AN:

68014

Other (OTH)

AF:

0.0511

AC:

108

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

444

887

1331

1774

2218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0560

Hom.:

Bravo

AF:

0.0682

Asia WGS

AF:

0.0350

AC:

123

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

0.26

(source)

DANN

Benign

0.25

PhyloP100

-0.65

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over