rs151228365

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002246.3(KCNK3):c.423C>A(p.His141Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00077 in 1,611,298 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.00096 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00075 ( 1 hom. )

Consequence

KCNK3
NM_002246.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.66

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pulmonary hypertension, primary, 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
heritable pulmonary arterial hypertension
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011818379).

BP6

Variant 2-26727806-C-A is Benign according to our data. Variant chr2-26727806-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 474321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK3	NM_002246.3 link	c.423C>A	p.His141Gln	missense_variant	Exon 2 of 2	ENST00000302909.4	NP_002237.1
KCNK3	XM_005264293.3 link	c.93C>A	p.His31Gln	missense_variant	Exon 2 of 2		XP_005264350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK3	ENST00000302909.4 link	c.423C>A	p.His141Gln	missense_variant	Exon 2 of 2	1	NM_002246.3	ENSP00000306275.3

Frequencies

GnomAD3 genomes

AF:

0.000959

AC:

146

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000745

AC:

186

AN:

249766

AF XY:

0.000733

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00554

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000514

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.000751

AC:

1095

AN:

1458916

Hom.:

Cov.:

AF XY:

0.000746

AC XY:

541

AN XY:

725300

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33434

American (AMR)

AF:

0.00146

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00616

AC:

160

AN:

25992

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00643

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000661

AC:

734

AN:

1109902

Other (OTH)

AF:

0.00144

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

133

199

266

332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000958

AC:

146

AN:

152382

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41598

American (AMR)

AF:

0.00510

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68036

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000873

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.00125

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 4

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

KCNK3-related disorder

Benign:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;L

PhyloP100

2.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T

Sift4G

Benign

0.28

T;T

Vest4

0.49

ClinPred

0.040

GERP RS

4.4

Varity_R

0.58

gMVP

0.93

Mutation Taster

=14/86

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over