Genetic Variant KCNK3:p.Arg318Leu (chr2-26728336-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002246.3(KCNK3):c.953G>T(p.Arg318Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNK3
NM_002246.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.50

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3007648).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002246.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK3	NM_002246.3	MANE Select	c.953G>T	p.Arg318Leu	missense	Exon 2 of 2	NP_002237.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK3	ENST00000302909.4	TSL:1 MANE Select	c.953G>T	p.Arg318Leu	missense	Exon 2 of 2	ENSP00000306275.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451940

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721460

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.00

AC:

AN:

43768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39214

South Asian (SAS)

AF:

0.00

AC:

AN:

84694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107664

Other (OTH)

AF:

0.00

AC:

AN:

59970

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.068

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

3.5

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.13

Sift

Uncertain

0.023

Sift4G

Uncertain

0.032

Polyphen

0.93

Vest4

0.40

MutPred

0.43

Loss of sheet (P = 0.0357)

MVP

0.50

ClinPred

0.98

GERP RS

4.1

Varity_R

0.27

gMVP

0.84

Mutation Taster

=69/31

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over