dbSNP rs1085307438: KCNK3:p.Thr8Lys (chr2-26692898-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_002246.3(KCNK3):c.23C>A(p.Thr8Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNK3
NM_002246.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.20

Publications

7 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:

ENSG00000295291 (HGNC:):

ENSG00000295291 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a mutagenesis_site No effect on channel basal activity. (size 0) in uniprot entity KCNK3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 2-26692898-C-A is Pathogenic according to our data. Variant chr2-26692898-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 426049.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK3	NM_002246.3 link	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 2	ENST00000302909.4	NP_002237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK3	ENST00000302909.4 link	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 2	1	NM_002246.3	ENSP00000306275.3
ENSG00000295291	ENST00000729046.1 link	n.108+32G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1330494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

652432

African (AFR)

AF:

0.00

AC:

AN:

27156

American (AMR)

AF:

0.00

AC:

AN:

31256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23612

East Asian (EAS)

AF:

0.00

AC:

AN:

30236

South Asian (SAS)

AF:

0.00

AC:

AN:

74106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3902

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046806

Other (OTH)

AF:

0.00

AC:

AN:

55016

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 4

Pathogenic:1

Rare Disease Genomics Group, St George's University of London

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.58

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.8

PhyloP100

5.2

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Vest4

0.90

ClinPred

1.0

GERP RS

2.2

PromoterAI

0.047

Neutral

(source)

Varity_R

0.89

gMVP

0.97

Mutation Taster

=12/88

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over