chr2-135851076-G-A

Variant names:

• chr2-135851076-G-A
• rs4988235
• NM_005915.6:c.1917+326C>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+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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MCM6	NM_005915.6	c.1917+326C>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+326C>T		intron_variant	Intron 13 of 16	1	NM_005915.6	ENSP00000264156.2
MCM6	ENST00000483902.1	n.544+326C>T		intron_variant	Intron 1 of 1	2
MCM6	ENST00000492091.1	n.343+326C>T		intron_variant	Intron 3 of 5	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

African (AFR) AF: 0.121 AC: 5025 AN: 41510

American (AMR) AF: 0.227 AC: 3476 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3468

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.163 AC: 788 AN: 4820

European-Finnish (FIN) AF: 0.577 AC: 6091 AN: 10548

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43184 AN: 67976

Other (OTH) AF: 0.291 AC: 614 AN: 2110

Alfa AF: 0.472 Hom.: 36766

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

Jan 26, 2021

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

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iDNA Genomics

Significance: association

Review Status: no assertion criteria provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs4988235; hg19: chr2-136608646;