rs541915908

Positions:

• chr10-117209504-C-CT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_181840.1(KCNK18):​c.361dupT​(p.Tyr121fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,916 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (39 hom.)
• Consequence: KCNK18 NM_181840.1 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 1.17

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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000775 (118/152258) while in subpopulation SAS AF= 0.0195 (94/4812). AF 95% confidence interval is 0.0163. There are 1 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK18	NM_181840.1	c.361dupT	p.Tyr121fs	frameshift_variant	3/3	ENST00000334549.1	NP_862823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK18	ENST00000334549.1	c.361dupT	p.Tyr121fs	frameshift_variant	3/3	1	NM_181840.1	ENSP00000334650.1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00263 AC: 659 AN: 250950 Hom.: 12 AF XY: 0.00345 AC XY: 468 AN XY: 135774

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00150 AC: 2188 AN: 1461658 Hom.: 39 Cov.: 33 AF XY: 0.00207 AC XY: 1506 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00854

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous duplication variant was identified, NM_181840.1(KCNK18):c.361dupT in exon 3 of 3 of the KCNK18 gene. This duplication is predicted to cause a frameshift from amino acid position 121 introducing a stop codon 44 residues downstream, NP_862823.1(KCNK18):p.(Tyr121Leufs*44), resulting in a truncated protein. The variant is present in the gnomAD population database at a frequency of 1.9% (561 heterozygotes, 11 homozygotes) in the South Asian subpopulation. It has been previously reported as likely pathogenic (ClinVar) and with questionable disease contribution (Gardiner, 2016). In addition, functional studies show that this variant produces a new isoform capable of repressing TREK1 and TREK2, however the mechanism of this activity is also questionable (Royal, P. et al. (2019)). There are no other downstream variants predicted to cause a truncated protein that have been reported as pathogenic in individuals with this condition (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs541915908; hg19: chr10-118969015;