rs4988235

Positions:

• chr2-135851076-G-A
• chr2-135851076-G-C
• chr2-135851076-G-T

Variant summary

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

The NM_005915.6(MCM6):​c.1917+326C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,102 control chromosomes in the GnomAD database, including 17,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.40 (17494 hom., cov: 32)
• Consequence: MCM6 NM_005915.6 intron
• Clinical Significance: association no assertion criteria provided O:2
• Conservation: PhyloP100: 0.00800

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=-0.56).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1917+326C>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.1917+326C>T		intron_variant		1	NM_005915.6	ENSP00000264156	P1
MCM6	ENST00000483902.1	n.544+326C>T		intron_variant, non_coding_transcript_variant		2
MCM6	ENST00000492091.1	n.343+326C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60370 AN: 151984 Hom.: 17499 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.294

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

GnomAD4 genome AF: 0.397 AC: 60356 AN: 152102 Hom.: 17494 Cov.: 32 AF XY: 0.381 AC XY: 28329 AN XY: 74344

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.291

Alfa AF: 0.505 Hom.: 24250

Bravo AF: 0.359

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Lactase persistence Other:2

association, no assertion criteria provided	reference population	iDNA Genomics	-	- -
association, no assertion criteria provided	literature only	OMIM	Jan 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.91

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: rs4988235; hg19: chr2-136608646;