rs368524386

Positions:

chr2-26728215-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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 (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

KCNK3
NM_002246.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.61

Variant links:

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]

KCNK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
KCNK3	NM_002246.3 linkuse as main transcript	c.832A>T	p.Ser278Cys	missense_variant	2/2	ENST00000302909.4	NP_002237.1
KCNK3	XM_005264293.3 linkuse as main transcript	c.502A>T	p.Ser168Cys	missense_variant	2/2		XP_005264350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK3	ENST00000302909.4 linkuse as main transcript	c.832A>T	p.Ser278Cys	missense_variant	2/2	1	NM_002246.3	ENSP00000306275	P1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

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:

AN:

162258

Hom.:

AF XY:

0.000283

AC XY:

AN XY:

88292

show subpopulations

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.:

Cov.:

AF XY:

0.000274

AC XY:

191

AN XY:

697230

show subpopulations

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:

AN:

151998

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74264

show subpopulations

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.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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: â€¢ 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 â€œOtherâ€, 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

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.12

.;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.74

.;N

REVEL

Benign

0.040

Sift

Benign

0.062

.;T

Sift4G

Benign

0.11

T;T

Polyphen

0.45

.;P

Vest4

0.30

MVP

0.40

ClinPred

0.014

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

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