2-135864646-T-C

Variant names:

• chr2-135864646-T-C
• rs309176
• NM_005915.6:c.1078+367A>G

Variant summary

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

The NM_005915.6(MCM6):​c.1078+367A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,028 control chromosomes in the GnomAD database, including 23,211 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: 32)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.313
• Publications: 4 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 = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1078+367A>G		intron_variant	Intron 7 of 16	ENST00000264156.3	NP_005906.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM6	ENST00000264156.3	c.1078+367A>G		intron_variant	Intron 7 of 16	1	NM_005915.6	ENSP00000264156.2
MCM6	ENST00000492091.1	n.39+367A>G		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76188 AN: 151910 Hom.: 23210 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.237

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: 0.501 AC: 76201 AN: 152028 Hom.: 23211 Cov.: 32 AF XY: 0.493 AC XY: 36605 AN XY: 74296

African (AFR) AF: 0.217 AC: 9010 AN: 41460

American (AMR) AF: 0.392 AC: 5991 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3460

East Asian (EAS) AF: 0.361 AC: 1865 AN: 5160

South Asian (SAS) AF: 0.346 AC: 1668 AN: 4816

European-Finnish (FIN) AF: 0.697 AC: 7360 AN: 10558

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47637 AN: 67960

Other (OTH) AF: 0.429 AC: 906 AN: 2114

Alfa AF: 0.593 Hom.: 7950

Bravo AF: 0.468

Asia WGS AF: 0.370 AC: 1289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.7
DANN	Benign	0.45
PhyloP100		-0.31
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: rs309176; hg19: chr2-136622216;