17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_017777.4(MKS1):c.1408-34_1408-6del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,611,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 0 hom. )
Consequence
MKS1
NM_017777.4 splice_region, splice_polypyrimidine_tract, intron
NM_017777.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.22
Genes affected
MKS1 (HGNC:7121): (MKS transition zone complex subunit 1) The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G is Pathogenic according to our data. Variant chr17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 188400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MKS1 | NM_017777.4 | c.1408-34_1408-6del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000393119.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MKS1 | ENST00000393119.7 | c.1408-34_1408-6del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_017777.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00120 AC: 183AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00105 AC: 260AN: 246468Hom.: 0 AF XY: 0.000949 AC XY: 127AN XY: 133848
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GnomAD4 exome AF: 0.00110 AC: 1602AN: 1459406Hom.: 0 AF XY: 0.00107 AC XY: 779AN XY: 726056
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GnomAD4 genome AF: 0.00120 AC: 183AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105AN XY: 74304
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Meckel syndrome, type 1 Pathogenic:6
Pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 20, 2023 | Variant summary: MKS1 c.1408-34_1408-6del29 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 246468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1, allowing no conclusion about variant significance. c.1408-34_1408-6del29 has been reported in the literature in individuals affected with Meckel Syndrome Type 1. These data indicate that the variant is likely to be associated with disease. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=11, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | NM_017777.3(MKS1):c.1408-34_1408-6del29 is classified as pathogenic in the context of MKS1-related disorders. Sources cited for classification include the following: PMID 16415886 and 23351400. Classification of NM_017777.3(MKS1):c.1408-34_1408-6del29 is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2007 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2022 | Described as a founder mutation in the Finnish population and many other European populations (Kyttala et al., 2006; Frank et al., 2007); Published functional studies demonstrate abnormal gene splicing (Kyttala et al., 2006); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17377820, 23351400, 17437276, 17935508, 16415886, 17397051, 27377014, 29096034) - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 29, 2019 | DNA sequence analysis of the MKS1 gene demonstrated a 29 bp-deletion in intron 15, c.1408-34_1408-6del. This intronic change is a founder mutation in the Finnish population and a known cause of Meckel-Gruber syndrome. It has been reported in the homozygous and compound heterozygous state in multiple affected individuals (PMIDs: 16415886, 17935508, 17397051). Functional studies in an affected individual's fibroblasts have demonstrated that this variant disrupts mRNA splicing leading to a premature stop codon and a truncated or absent protein (PMID: 16415886). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | MKS1: PM3:Very Strong, PM2, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 11, 2017 | - - |
Joubert syndrome 28 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Apr 08, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 29, 2017 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change falls in intron 15 of the MKS1 gene. It does not directly change the encoded amino acid sequence of the MKS1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs749737706, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 16415886, 17377820, 17397051, 17437276, 17935508). It is commonly reported in individuals of Finnish ancestry (PMID: 23351400). ClinVar contains an entry for this variant (Variation ID: 188400). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 16 and introduces a new termination codon (PMID: 16415886). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Bardet-Biedl syndrome 13 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The c.1408-34_1408-6del29 alteration is located in intron 15 of the MKS1 gene. This alteration consists of a deletion of 29 nucleotides at nucleotide position c.1408-34 to c.1408-6. This mutation has been identified in the homozygous state in multiple Meckel syndrome families and is considered a founder mutation in the Finnish population (Kyttälä, 2006). It has also been reported in several other individuals in the homozygous or compound heterozygous state with Meckel syndrome or a MKS1-related ciliopathy (Consugar, 2007; Szymanska, 2012; Bader, 2016). Analysis of fibroblasts from an individual homozygous for this mutation demonstrated aberrant splicing (Kyttälä, 2006). Based on the available evidence, this alteration is classified as pathogenic. - |
MKS1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2024 | The MKS1 c.1408-34_1408-6del29 variant is predicted to result in an intronic deletion. This deletion has been shown to disrupt splicing of MKS1 and cause Meckel-Gruber syndrome in multiple unrelated individuals when found in the homozygous or compound heterozygous states (reported as IVS15-7_35del in Table 1, Kyttala et al. 2006. PubMed ID: 16415886; reported as c.1408-35_1408-7del29, Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.70% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, this variant is reported as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/188400/). This variant is interpreted as pathogenic. - |
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Universitätsklinikum Salzburg, Universitätskinderklinik | Jun 19, 2016 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at