rs201998680
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_017777.4(MKS1):c.1014G>A(p.Leu338Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,613,692 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00059 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00077 ( 16 hom. )
Consequence
MKS1
NM_017777.4 synonymous
NM_017777.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.886
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 Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.3).
BP6
Variant 17-58210669-C-T is Benign according to our data. Variant chr17-58210669-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260878.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000591 (90/152278) while in subpopulation SAS AF= 0.0174 (84/4826). AF 95% confidence interval is 0.0144. There are 4 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MKS1 | NM_017777.4 | c.1014G>A | p.Leu338Leu | synonymous_variant | 11/18 | ENST00000393119.7 | NP_060247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MKS1 | ENST00000393119.7 | c.1014G>A | p.Leu338Leu | synonymous_variant | 11/18 | 1 | NM_017777.4 | ENSP00000376827.2 |
Frequencies
GnomAD3 genomes AF: 0.000591 AC: 90AN: 152160Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.00154 AC: 383AN: 249508Hom.: 7 AF XY: 0.00198 AC XY: 268AN XY: 135360
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GnomAD4 exome AF: 0.000766 AC: 1119AN: 1461414Hom.: 16 Cov.: 31 AF XY: 0.00108 AC XY: 787AN XY: 727056
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GnomAD4 genome AF: 0.000591 AC: 90AN: 152278Hom.: 4 Cov.: 32 AF XY: 0.000859 AC XY: 64AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Meckel syndrome, type 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | MKS1: BP4, BP7, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2020 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Bardet-Biedl syndrome 13 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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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