rs1553383771

Variant names:

• chr2-26692975-G-A
• rs1553383771
• NM_002246.3:c.100G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26692975-G-A
• chr2-26692975-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002246.3(KCNK3):​c.100G>A​(p.Glu34Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E34D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• Publications: 0 publications found

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

ENSG00000295291 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK3	NM_002246.3	c.100G>A	p.Glu34Lys	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	c.100G>A	p.Glu34Lys	missense_variant	Exon 1 of 2	1	NM_002246.3	ENSP00000306275.3
ENSG00000295291	ENST00000729046.1	n.63C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418936 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 703344

African (AFR) AF: 0.00 AC: 0 AN: 32258

American (AMR) AF: 0.00 AC: 0 AN: 39552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 37154

South Asian (SAS) AF: 0.00 AC: 0 AN: 82092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4962

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1094930

Other (OTH) AF: 0.00 AC: 0 AN: 58814

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 4 Uncertain:1

Jun 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 34 of the KCNK3 protein (p.Glu34Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a KCNK3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on KCNK3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.60		Gain of methylation at E34 (P = 0.0228);
MVP		0.64
ClinPred		0.99	D
GERP RS		3.2
PromoterAI		0.031	Neutral
Varity_R		0.92
gMVP		0.98
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs1553383771; hg19: chr2-26915843;