chr2-47806412-C-G
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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
NM_000179.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.00
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]
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]
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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 | c.3802-40C>G | intron_variant | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3802-40C>G | intron_variant | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.772 AC: 117396AN: 151974Hom.: 46108 Cov.: 32
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GnomAD3 exomes AF: 0.734 AC: 184101AN: 250824Hom.: 68350 AF XY: 0.733 AC XY: 99392AN XY: 135650
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GnomAD4 exome AF: 0.738 AC: 1078548AN: 1461572Hom.: 399652 Cov.: 45 AF XY: 0.736 AC XY: 535403AN XY: 727108
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GnomAD4 genome AF: 0.772 AC: 117488AN: 152092Hom.: 46154 Cov.: 32 AF XY: 0.767 AC XY: 57039AN XY: 74322
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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
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Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at