2-47806412-C-G

Position:

chr2-47806412-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000179.3(MSH6):c.3802-40C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,613,664 control chromosomes in the GnomAD database, including 445,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.77 ( 46154 hom., cov: 32)

Exomes 𝑓: 0.74 ( 399652 hom. )

Consequence

MSH6
NM_000179.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:9

Conservation

PhyloP100: -1.00

Variant links:

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

MSH6 links:

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-47806412-C-G is Benign according to our data. Variant chr2-47806412-C-G is described in ClinVar as [Benign]. Clinvar id is 36594.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806412-C-G is described in Lovd as [Benign]. Variant chr2-47806412-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3802-40C>G		intron_variant		ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.3802-40C>G		intron_variant		1	NM_000179.3	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.772

AC:

117396

AN:

151974

Hom.:

46108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.915

Gnomad AMI

AF:

0.728

Gnomad AMR

AF:

0.660

Gnomad ASJ

AF:

0.763

Gnomad EAS

AF:

0.875

Gnomad SAS

AF:

0.755

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.725

Gnomad OTH

AF:

0.745

GnomAD3 exomes

AF:

0.734

AC:

184101

AN:

250824

Hom.:

68350

AF XY:

0.733

AC XY:

99392

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.919

Gnomad AMR exome

AF:

0.616

Gnomad ASJ exome

AF:

0.764

Gnomad EAS exome

AF:

0.883

Gnomad SAS exome

AF:

0.740

Gnomad FIN exome

AF:

0.662

Gnomad NFE exome

AF:

0.730

Gnomad OTH exome

AF:

0.719

GnomAD4 exome

AF:

0.738

AC:

1078548

AN:

1461572

Hom.:

399652

Cov.:

AF XY:

0.736

AC XY:

535403

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.917

Gnomad4 AMR exome

AF:

0.622

Gnomad4 ASJ exome

AF:

0.763

Gnomad4 EAS exome

AF:

0.872

Gnomad4 SAS exome

AF:

0.739

Gnomad4 FIN exome

AF:

0.665

Gnomad4 NFE exome

AF:

0.735

Gnomad4 OTH exome

AF:

0.740

GnomAD4 genome

AF:

0.772

AC:

117488

AN:

152092

Hom.:

46154

Cov.:

AF XY:

0.767

AC XY:

57039

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.915

Gnomad4 AMR

AF:

0.660

Gnomad4 ASJ

AF:

0.763

Gnomad4 EAS

AF:

0.875

Gnomad4 SAS

AF:

0.755

Gnomad4 FIN

AF:

0.653

Gnomad4 NFE

AF:

0.725

Gnomad4 OTH

AF:

0.741

Alfa

AF:

0.700

Hom.:

4302

Bravo

AF:

0.780

Asia WGS

AF:

0.807

AC:

2810

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Lynch syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Lynch syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.42

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over