rs869025175

Variant names:

• chr10-117209553-GCT-G
• rs869025175
• NM_181840.1:c.414_415delCT

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:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: KCNK18 NM_181840.1 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 O:1
• Conservation: PhyloP100: 7.60

Genes affected

KCNK18 (HGNC:19439): (potassium two pore domain channel subfamily K member 18) Potassium channels play a role in many cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. This gene encodes a member of the superfamily of potassium channel proteins containing two pore-forming P domains and the encoded protein functions as an outward rectifying potassium channel. A mutation in this gene has been found to be associated with migraine with aura.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK18	NM_181840.1	c.414_415delCT	p.Phe139TrpfsTer25	frameshift_variant	Exon 3 of 3	ENST00000334549.1	NP_862823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK18	ENST00000334549.1	c.414_415delCT	p.Phe139TrpfsTer25	frameshift_variant	Exon 3 of 3	1	NM_181840.1	ENSP00000334650.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000437 AC: 110 AN: 251476 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000499 AC: 730 AN: 1461886 Hom.: 1 AF XY: 0.000539 AC XY: 392 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000601

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74450

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000400

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Dec 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNK18: PP1:Strong, PS3:Supporting -

Mar 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Migraine, with or without aura, susceptibility to, 13 Pathogenic:1 Other:1

Jul 28, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Jun 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025175; hg19: chr10-118969064;