rs4954490

Variant names:

• chr2-135850661-G-A
• rs4954490
• NM_005915.6:c.1917+741C>T

Variant summary

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

The NM_005915.6(MCM6):​c.1917+741C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 152,058 control chromosomes in the GnomAD database, including 23,805 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 0.51 (23805 hom., cov: 32)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628
• Publications: 16 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1917+741C>T		intron_variant	Intron 13 of 16	ENST00000264156.3	NP_005906.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM6	ENST00000264156.3	c.1917+741C>T		intron_variant	Intron 13 of 16	1	NM_005915.6	ENSP00000264156.2
MCM6	ENST00000483902.1	n.544+741C>T		intron_variant	Intron 1 of 1	2
MCM6	ENST00000492091.1	n.343+741C>T		intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77296 AN: 151940 Hom.: 23803 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.508 AC: 77315 AN: 152058 Hom.: 23805 Cov.: 32 AF XY: 0.500 AC XY: 37196 AN XY: 74336

African (AFR) AF: 0.220 AC: 9137 AN: 41452

American (AMR) AF: 0.400 AC: 6112 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1047 AN: 3468

East Asian (EAS) AF: 0.359 AC: 1858 AN: 5174

South Asian (SAS) AF: 0.375 AC: 1807 AN: 4820

European-Finnish (FIN) AF: 0.710 AC: 7505 AN: 10568

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 48151 AN: 67978

Other (OTH) AF: 0.437 AC: 922 AN: 2108

Alfa AF: 0.609 Hom.: 15135

Bravo AF: 0.475

Asia WGS AF: 0.381 AC: 1327 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		0.63
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: rs4954490; hg19: chr2-136608231;