rs398123043

Positions:

• chr2-26727958-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000302909.4(KCNK3):​c.575A>G​(p.Tyr192Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNK3 ENST00000302909.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.24

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a intramembrane_region Pore-forming; Name=Pore-forming 2 (size 23) in uniprot entity KCNK3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000302909.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 2-26727958-A-G is Pathogenic according to our data. Variant chr2-26727958-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 60483.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK3	NM_002246.3	c.575A>G	p.Tyr192Cys	missense_variant	2/2	ENST00000302909.4	NP_002237.1
KCNK3	XM_005264293.3	c.245A>G	p.Tyr82Cys	missense_variant	2/2		XP_005264350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK3	ENST00000302909.4	c.575A>G	p.Tyr192Cys	missense_variant	2/2	1	NM_002246.3	ENSP00000306275	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary hypertension, primary, 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 25, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.8	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.5	.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.73		.;Gain of sheet (P = 0.1208);
MVP		0.60
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.99

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: rs398123043; hg19: chr2-26950826;