2-47806652-GTAACTAACTAACTATAATGGAATTA-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_ModerateBP6_Very_Strong
The NM_000179.3(MSH6):c.4001+11_4001+35del variant causes a splice donor, splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,607,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
MSH6
NM_000179.3 splice_donor, splice_donor_5th_base, intron
NM_000179.3 splice_donor, splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.29
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 Likely_benign. Variant got -6 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.048738673 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.2, offset of 0 (no position change), new splice context is: tcgGTaact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
BP6
Variant 2-47806652-GTAACTAACTAACTATAATGGAATTA-G is Benign according to our data. Variant chr2-47806652-GTAACTAACTAACTATAATGGAATTA-G is described in ClinVar as [Likely_benign]. Clinvar id is 237203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47806652-GTAACTAACTAACTATAATGGAATTA-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.4001+11_4001+35del | splice_donor_variant, splice_donor_5th_base_variant, intron_variant | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.4001+11_4001+35del | splice_donor_variant, splice_donor_5th_base_variant, intron_variant | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151882Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000205 AC: 5AN: 244224Hom.: 0 AF XY: 0.0000302 AC XY: 4AN XY: 132416
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GnomAD4 exome AF: 0.0000179 AC: 26AN: 1455198Hom.: 0 AF XY: 0.0000221 AC XY: 16AN XY: 724206
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151882Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74180
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2020 | 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 | Nov 17, 2015 | - - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2018 | This variant is associated with the following publications: (PMID: 26483394) - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at