Variant rs869025175 details in Genebe, Genetics Data Aggregator

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.Phe139fs) 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 7.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
KCNK18	NM_181840.1 linkuse as main transcript	c.414_415delCT	p.Phe139fs	frameshift_variant	3/3	ENST00000334549.1	NP_862823.1	Q7Z418

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK18	ENST00000334549.1 linkuse as main transcript	c.414_415delCT	p.Phe139fs	frameshift_variant	3/3	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

GnomAD3 exomes

AF:

0.000437

AC:

110

AN:

251476

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

135920

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 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.:

AF XY:

0.000539

AC XY:

392

AN XY:

727246

show subpopulations

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:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74450

show subpopulations

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.:

Bravo

AF:

0.000400

EpiCase

AF:

0.000600

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	Segregates with typical migraine with visual aura in a single family in the published literature (Lafreniere et al., 2010); Frameshift variant predicted to result in protein truncation in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 20871611, 23904616, 31589614, 31742594, 30573346, 35806193) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KCNK18: PP1:Strong, PS3:Supporting -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 25, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2024

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

risk factor, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over