rs368524386

Positions:

• chr2-26728215-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002246.3(KCNK3):​c.832A>T​(p.Ser278Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,562,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S278R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.61

Genes affected

KCNK3 (HGNC:6278): (potassium two pore domain channel subfamily K member 3) This gene encodes a member of the superfamily of potassium channel proteins that contain two pore-forming P domains. The encoded protein is an outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane. Although three transcripts are detected in northern blots, there is currently no sequence available to confirm transcript variants for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09628177).
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK3	NM_002246.3	c.832A>T	p.Ser278Cys	missense_variant	2/2	ENST00000302909.4
KCNK3	XM_005264293.3	c.502A>T	p.Ser168Cys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK3	ENST00000302909.4	c.832A>T	p.Ser278Cys	missense_variant	2/2	1	NM_002246.3	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151998 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000222 AC: 36 AN: 162258 Hom.: 0 AF XY: 0.000283 AC XY: 25 AN XY: 88292

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000526

Gnomad FIN exome AF: 0.0000684

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000253 AC: 357 AN: 1410390 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 191 AN XY: 697230

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000528

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.000206

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151998 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74264

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000181 AC: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary hypertension, primary, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 278 of the KCNK3 protein (p.Ser278Cys). This variant is present in population databases (rs368524386, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KCNK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 541325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNK3 protein function with a negative predictive value of 80%. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.832A>T (p.S278C) alteration is located in exon 2 (coding exon 2) of the KCNK3 gene. This alteration results from a A to T substitution at nucleotide position 832, causing the serine (S) at amino acid position 278 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Sep 28, 2017

Found in a previously healthy 16-year-old male who died in his sleep, with a negative autopsy. He had postmortem genetic testing for Arrhythmias, Cardiomyopathies, and Sudden Death in Epilepsy with the Invitae laboratory. Results showed one variant: • p.Ser278Cys (S278C; c.832A>T) in the KCNK3 gene The KCNK3 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant pulmonary arterial hypertension (PMID: 23883380, 24742047). This was not our patient's phenotype. p.Ser278Cys (S278C; c.832A>T) in exon 2 of the KCNK3 gene (NM_002246.2) Chromosome position 2:26951083 A / T Based on the information reviewed below, we classify this as a Variant of Unknown Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a polar Serine with a polar Cysteine capable of forming disulfide bridges. Serine at this location is extremely poorly conserved across ~100 vertebrate species for which we have data. In fact, Cysteine is the default amino acid in at least 12 mammalian species. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". This variant was reported in 37 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 13/12,420 South Asians (for the highest allele frequency: 0.052%), 17/37,446 non-Finnish Europeans (MAF 0.023%), 3 Latinos, 2 “Other”, and 1 Finnish European and 1 African individual. Overall MAF 0.02%. Our patient's ancestry is Caucasian. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	0.11	T;T
Polyphen		0.45	.;P
Vest4		0.30
MVP		0.40
ClinPred		0.014	T
GERP RS		2.1
Varity_R		0.064
gMVP		0.68

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: rs368524386; hg19: chr2-26951083; COSMIC: COSV57194852;