rs869025175

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

KCNK18
NM_181840.1 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6O:1

Conservation

PhyloP100: 7.60

Publications

30 publications found

Variant links:

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]

KCNK18 Gene-Disease associations (from GenCC):

migraine, with or without aura, susceptibility to, 13
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

KCNK18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 66 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK18	NM_181840.1 link	c.414_415delCT	p.Phe139TrpfsTer25	frameshift_variant	Exon 3 of 3	ENST00000334549.1	NP_862823.1	Q7Z418

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK18	ENST00000334549.1 link	c.414_415delCT	p.Phe139TrpfsTer25	frameshift_variant	Exon 3 of 3	1	NM_181840.1	ENSP00000334650.1		Q7Z418

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000437

AC:

110

AN:

251476

AF XY:

0.000515

show subpopulations

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 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.:

AF XY:

0.000539

AC XY:

392

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000313

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000393

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000601

AC:

668

AN:

1112004

Other (OTH)

AF:

0.000348

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000434

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41530

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68014

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000400

EpiCase

AF:

0.000600

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

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. -

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) -

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 -

Migraine, with or without aura, susceptibility to, 13

Pathogenic:1Other: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. -

Parkinson disease;C0242422:Parkinsonian disorder;C0393568:Vascular parkinsonism

Uncertain:1

Oct 01, 2024

The Egyptian Network for Neurodegenerative Diseases (ENND), The American University in Cairo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

This rare variant (MAF 0/0.0004 in 1000Genomes and GnomAD) classified as VUS according to ACMG is associated with autosomal dominant migraine with aura (MGR13) as identified in a 4-generation family due to same heterozygous frameshift 2-bp deletion (414delCT) and premature termination in the second transmembrane domain in the KCNK18 gene (PMID:20871611), Functional expression studies in Xenopus oocytes showed that the mutant protein resulted in a lack of potassium currents and acted in a dominant-negative fashion when coexpressed with the wildtype protein. Migraine with aura (MWA) is a risk factor for both ischemic and hemorrhagic stroke. MWA is generally the first symptom and is present in 30–40% of CADASIL patients, which phenotypically overlaps with vascular parkinsonism. Several studies have showed significant associations between MWA and parkinsonism; therefore we suspect this variant could be contributing to vascular parkinsonism observed in one patient extending the phenotype spectrum of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.6

Mutation Taster

=20/180

disease causing (ClinVar)

(source)

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

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rs869025175

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over