2-47806661-T-TAACTA
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_000179.3(MSH6):c.4001+11_4001+15dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,603,248 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 2 hom. )
Consequence
MSH6
NM_000179.3 intron
NM_000179.3 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.199
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 -9 ACMG points.
BP6
Variant 2-47806661-T-TAACTA is Benign according to our data. Variant chr2-47806661-T-TAACTA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89499.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000161 (234/1451956) while in subpopulation SAS AF= 0.001 (86/85990). AF 95% confidence interval is 0.000829. There are 2 homozygotes in gnomad4_exome. There are 147 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.4001+11_4001+15dup | intron_variant | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.4001+11_4001+15dup | intron_variant | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000218 AC: 33AN: 151292Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000214 AC: 52AN: 243512Hom.: 0 AF XY: 0.000265 AC XY: 35AN XY: 132136
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GnomAD4 exome AF: 0.000161 AC: 234AN: 1451956Hom.: 2 Cov.: 34 AF XY: 0.000203 AC XY: 147AN XY: 722882
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GnomAD4 genome AF: 0.000218 AC: 33AN: 151292Hom.: 0 Cov.: 32 AF XY: 0.000284 AC XY: 21AN XY: 73854
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 25, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 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, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Dec 21, 2021 | - - |
Benign, flagged submission | clinical testing | GeneDx | Oct 01, 2014 | The variant is found in BR-OV-HEREDIC,HEREDICANCER panel(s). - |
Lynch syndrome Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 c.4001+11_4001+15dup variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs730882138) as "With Likely benign, other allele" and ClinVar (classified as likely benign by Invitae, Counsyl and two other submitters). The variant was identified in control databases in 70 of 269486 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 23 of 30492 chromosomes (freq: 0.0008), European in 41 of 123358 chromosomes (freq: 0.0003), East Asian in 3 of 18612 chromosomes (freq: 0.0002), and Finnish in 3 of 23088 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, Latino, or Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 01, 2016 | Variant summary: The MSH6 c.4001+11_4001+15dupAACTA variant results into duplication of five non-conserved nucleotides in intron 9 at a region not widely known to involve in splicing. Mutation taster predicts a benign outcome for this variant. In addition, 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 29/111750 control chromosomes from ExAC at a frequency of 0.0002595, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature. Taken together, this variant is classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Lynch syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Feb 02, 2018 | - - |
Hereditary nonpolyposis colon cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2021 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at