chr17-58214760-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_017777.4(MKS1):c.496C>T(p.Arg166Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000971 in 1,606,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017777.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000180 AC: 44AN: 244194Hom.: 0 AF XY: 0.000150 AC XY: 20AN XY: 132960
GnomAD4 exome AF: 0.0000763 AC: 111AN: 1454432Hom.: 0 Cov.: 30 AF XY: 0.0000829 AC XY: 60AN XY: 723844
GnomAD4 genome AF: 0.000296 AC: 45AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74288
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: MKS1 c.496C>T (p.Arg166Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 244194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.496C>T has been reported in the literature in the compound heterozygous state in at least one individual affected with Meckel Syndrome Type 1 (e.g. Tallila_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19466712). ClinVar contains an entry for this variant (Variation ID: 291155). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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not provided Uncertain:2
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19466712) -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 166 of the MKS1 protein (p.Arg166Trp). This variant is present in population databases (rs201845154, gnomAD 0.1%). This missense change has been observed in individual(s) with Meckel syndrome (PMID: 19466712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 291155). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MKS1 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Meckel syndrome, type 1 Uncertain:1
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Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28 Uncertain:1
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MKS1-related disorder Uncertain:1
The MKS1 c.496C>T variant is predicted to result in the amino acid substitution p.Arg166Trp. This variant has been reported in the compound heterozygous state in a fetus with suspected Meckel syndrome (Tallila et al. 2009. PubMed ID: 19466712). This variant is reported in 0.14% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at