chr2-47799852-C-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1
The NM_000179.3(MSH6):c.1869C>T(p.Pro623=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )
Consequence
MSH6
NM_000179.3 synonymous
NM_000179.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.129
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 -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
Variant 2-47799852-C-T is Benign according to our data. Variant chr2-47799852-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 182663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000604 (92/152304) while in subpopulation AFR AF= 0.00214 (89/41566). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1869C>T | p.Pro623= | synonymous_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1869C>T | p.Pro623= | synonymous_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000598 AC: 91AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000240 AC: 60AN: 250400Hom.: 1 AF XY: 0.000229 AC XY: 31AN XY: 135646
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GnomAD4 exome AF: 0.000102 AC: 149AN: 1461852Hom.: 1 Cov.: 34 AF XY: 0.0000935 AC XY: 68AN XY: 727222
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 09, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 27, 2020 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 14, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2014 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2015 | - - |
Lynch syndrome 5 Benign:2
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 28, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 29, 2016 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Pro623= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database databases. The variant was identified in dbSNP (ID: rs141242295) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae and likely benign by Ambry Genetics, Counsyl and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (4x), UMD-LSDB (2x as UV), and in control databases in 77 (1 homozygous) of 276602 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 53 (1 homozygous) of 23906 chromosomes (freq: 0.002), Other in 1 of 6460 chromosomes (freq: 0.00002), Latino in 9 of 34400 chromosomes (freq: 0.0003), East Asian in 7 of 18854 chromosomes (freq: 0.0004), and South Asian in 7 of 30774 chromosomes (freq: 0.0002) while not observed in the European Non-Finnish, Ashkenazi Jewish and European Finnish populations. The p.Pro623= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at