rs2304369

Positions:

• chr2-135851750-G-A
• chr2-135851750-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.650

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1756-187C>T		intron_variant		ENST00000264156.3	NP_005906.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM6	ENST00000264156.3	c.1756-187C>T		intron_variant		1	NM_005915.6	ENSP00000264156	P1
MCM6	ENST00000483902.1	n.196C>T		non_coding_transcript_exon_variant	1/2	2
MCM6	ENST00000492091.1	n.182-187C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0628 AC: 9546 AN: 152110 Hom.: 576 Cov.: 32

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.: 5 AF XY: 0.0331 AC XY: 4577 AN XY: 138300

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.0349

Gnomad4 ASJ exome AF: 0.0531

Gnomad4 EAS exome AF: 0.0548

Gnomad4 SAS exome AF: 0.0154

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0406

GnomAD4 genome AF: 0.0628 AC: 9554 AN: 152228 Hom.: 573 Cov.: 32 AF XY: 0.0608 AC XY: 4525 AN XY: 74446

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0402

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.0602

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0527 Hom.: 46

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
DANN	Benign	0.25

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

LitVar

Other links and lift over

dbSNP: rs2304369; hg19: chr2-136609320;