rs869025175

Positions:

• chr10-117209553-GCT-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_181840.1(KCNK18):​c.414_415del​(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: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 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/exons	MANE	UniProt
KCNK18	NM_181840.1	c.414_415del	p.Phe139TrpfsTer25	frameshift_variant	3/3	ENST00000334549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK18	ENST00000334549.1	c.414_415del	p.Phe139TrpfsTer25	frameshift_variant	3/3	1	NM_181840.1	P1

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: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KCNK18: PP1:Strong, PS3:Supporting -
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	Invitae	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. -

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

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;