rs869025175
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_181840.1(KCNK18):c.414_415delCT(p.Phe139TrpfsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_181840.1 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000434 AC: 66AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000437 AC: 110AN: 251476Hom.: 0 AF XY: 0.000515 AC XY: 70AN XY: 135920
GnomAD4 exome AF: 0.000499 AC: 730AN: 1461886Hom.: 1 AF XY: 0.000539 AC XY: 392AN XY: 727246
GnomAD4 genome AF: 0.000434 AC: 66AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:3
KCNK18: PP1:Strong, PS3:Supporting -
Segregates with typical migraine with visual aura in a single family in the published literature (PMID: 20871611); Frameshift variant predicted to result in abnormal protein length as the last 246 amino acids are replaced with 24 different amino acids in a gene for which loss-of-function is not an established mechanism of disease; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 20871611, 23904616, 31589614, 37152446, 31742594, 30573346, 35806193, 36044383, 36800925, 37628876) -
This sequence change creates a premature translational stop signal (p.Phe139Trpfs*25) in the KCNK18 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 246 amino acid(s) of the KCNK18 protein. This variant is present in population databases (rs780712214, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with migraine (PMID: 20871611). ClinVar contains an entry for this variant (Variation ID: 18398). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects KCNK18 function (PMID: 573346, 31742594). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Variant summary: KCNK18 c.414_415delCT (p.Phe139TrpfsX25) results in a premature termination codon in the last exon, therefore it is predicted to escape nonsense mediated decay (NMD), but is expected remove a large part of the 384 amino acid long protein. On the other hand, upstream out-of-frame ATG triplets could be found, which if utilized, would bring into frame the sequence downstream of the frameshift, generating an N-terminally truncated and altered protein product, and this prediction is supported by in vitro functional studies (Royal_2019). The variant allele was found at a frequency of 0.00044 in 251476 control chromosomes (gnomAD v2.1). This frequency is not higher than the estimated maximum expected for a pathogenic variant in KCNK18 causing Migraine, With Or Without Aura, Susceptibility To, 13, allowing no conclusion about variant significance. The variant, c.414_415delCT, has been reported in the literature in a large family where it was found in individuals affected with Migraine, and was absent from unaffected family members (Lafreniere_2010). Authors of this study and others reported loss-of-function effect for this variant (i.e. reduction of current), which also interfered with normal channel activity in a dominant negative fashion (e.g. Lafreniere_2010, Liu_2013). On the other hand, later functional studies suggested an (additional) gain-of-function mechanism, caused by the protein product of an upstream start codon (ATG), resulting in a protein fragment which could interfere with the function of other channels (Royal_2019). These reports do not provide unequivocal conclusions about association of the variant with Migraine, With Or Without Aura, Susceptibility To, 13. On the other hand, a recent genome-wide association study (GWAS) observed this variant with equal frequency in controls and cases (i.e. in 196 controls, and 10 cases), concluding that there was no association between the presence of this variant and migraine susceptibility (Markel_2022). The following publications have been ascertained in the context of this evaluation (PMID: 20871611, 23904616, 30573346, 31742594, 36044383). ClinVar contains an entry for this variant (Variation ID: 18398). Based on the evidence outlined above, the variant was classified as uncertain significance. -
KCNK18-related disorder Uncertain:1
The KCNK18 c.414_415delCT variant is predicted to result in a frameshift and premature protein termination (p.Phe139Trpfs*25). This variant, also referred to as F139WfsX24 in the literature, was found to segregate with affected individuals in a large family with migraine (Lafrenière et al. 2010. PubMed ID: 20871611). Multiple functional studies in different cell lines have shown that this variant suppresses wild type channel function through a dominant negative effect (Lafrenière et al. 2010. PubMed ID: 20871611; referred to as the frameshift mutation or MT, Liu et al. 2013. PubMed ID: 23904616; Pettingill et al. 2019. PubMed ID: 31742594; referred to as TRESK MT, Royal et al. 2019. PubMed ID: 30573346). Despite the functional evidence, protein truncating variants have not been well documented in this gene (Human Gene Mutation Database), and the GenCC database classifies the association of KCNK18 with migraine as "limited" (https://search.thegencc.org/genes/HGNC:19439). This variant is reported in 0.079% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is higher than expected for a highly penetrant variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Migraine, with or without aura, susceptibility to, 13 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at