2-135845796-C-G

Variant names:

• chr2-135845796-C-G
• rs3769005
• NM_005915.6:c.2209+441G>C

Variant summary

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

The NM_005915.6(MCM6):​c.2209+441G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,066 control chromosomes in the GnomAD database, including 24,388 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 0.52 (24388 hom., cov: 32)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248
• Publications: 15 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 = 0.703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005915.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM6	NM_005915.6	MANE Select	c.2209+441G>C		intron	N/A	NP_005906.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM6	ENST00000264156.3	TSL:1 MANE Select	c.2209+441G>C		intron	N/A	ENSP00000264156.2
	MCM6	ENST00000492091.1	TSL:5	n.635+441G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79618 AN: 151948 Hom.: 24380 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.457

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.524 AC: 79670 AN: 152066 Hom.: 24388 Cov.: 32 AF XY: 0.515 AC XY: 38317 AN XY: 74330

African (AFR) AF: 0.274 AC: 11371 AN: 41474

American (AMR) AF: 0.405 AC: 6187 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1046 AN: 3470

East Asian (EAS) AF: 0.359 AC: 1857 AN: 5172

South Asian (SAS) AF: 0.375 AC: 1809 AN: 4826

European-Finnish (FIN) AF: 0.710 AC: 7506 AN: 10568

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48161 AN: 67970

Other (OTH) AF: 0.452 AC: 956 AN: 2114

Alfa AF: 0.589 Hom.: 3562

Bravo AF: 0.494

Asia WGS AF: 0.385 AC: 1338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.9
DANN	Benign	0.36
PhyloP100		0.25
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: rs3769005; hg19: chr2-136603366;