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GeneBe

2-135844626-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_005915.6(MCM6):c.2268C>T(p.Ile756=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,585,624 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0034 ( 4 hom., cov: 31)
Exomes 𝑓: 0.0035 ( 23 hom. )

Consequence

MCM6
NM_005915.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.955
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-135844626-G-A is Benign according to our data. Variant chr2-135844626-G-A is described in ClinVar as [Benign]. Clinvar id is 781948.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.955 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 517 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MCM6NM_005915.6 linkuse as main transcriptc.2268C>T p.Ile756= synonymous_variant 16/17 ENST00000264156.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MCM6ENST00000264156.3 linkuse as main transcriptc.2268C>T p.Ile756= synonymous_variant 16/171 NM_005915.6 P1
MCM6ENST00000492091.1 linkuse as main transcriptn.694C>T non_coding_transcript_exon_variant 6/65

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00341
AC:
517
AN:
151818
Hom.:
4
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000339
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.0116
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00313
Gnomad FIN
AF:
0.00997
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00449
Gnomad OTH
AF:
0.00432
GnomAD3 exomes
AF:
0.00382
AC:
888
AN:
232360
Hom.:
4
AF XY:
0.00423
AC XY:
532
AN XY:
125762
show subpopulations
Gnomad AFR exome
AF:
0.000327
Gnomad AMR exome
AF:
0.00116
Gnomad ASJ exome
AF:
0.0102
Gnomad EAS exome
AF:
0.0000598
Gnomad SAS exome
AF:
0.00272
Gnomad FIN exome
AF:
0.00798
Gnomad NFE exome
AF:
0.00449
Gnomad OTH exome
AF:
0.00401
GnomAD4 exome
AF:
0.00349
AC:
5006
AN:
1433688
Hom.:
23
Cov.:
31
AF XY:
0.00370
AC XY:
2634
AN XY:
712058
show subpopulations
Gnomad4 AFR exome
AF:
0.000432
Gnomad4 AMR exome
AF:
0.00117
Gnomad4 ASJ exome
AF:
0.00964
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00281
Gnomad4 FIN exome
AF:
0.00823
Gnomad4 NFE exome
AF:
0.00347
Gnomad4 OTH exome
AF:
0.00344
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00340
AC:
517
AN:
151936
Hom.:
4
Cov.:
31
AF XY:
0.00330
AC XY:
245
AN XY:
74232
show subpopulations
Gnomad4 AFR
AF:
0.000338
Gnomad4 AMR
AF:
0.00164
Gnomad4 ASJ
AF:
0.0116
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.00313
Gnomad4 FIN
AF:
0.00997
Gnomad4 NFE
AF:
0.00449
Gnomad4 OTH
AF:
0.00427
Alfa
AF:
0.00407
Hom.:
2
Bravo
AF:
0.00250
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
Cadd
Benign
5.8
Dann
Benign
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4988270; hg19: chr2-136602196; API