chr2-26728563-G-A

Variant names:

• chr2-26728563-G-A
• rs1553387738
• NM_002246.3:c.1180G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002246.3(KCNK3):​c.1180G>A​(p.Val394Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000155 in 1,293,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V394A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• 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

ACMG classification

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=0.3162673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK3	NM_002246.3	c.1180G>A	p.Val394Met	missense_variant	Exon 2 of 2	ENST00000302909.4	NP_002237.1
KCNK3	XM_005264293.3	c.850G>A	p.Val284Met	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	c.1180G>A	p.Val394Met	missense_variant	Exon 2 of 2	1	NM_002246.3	ENSP00000306275.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1293946 Hom.: 0 Cov.: 30 AF XY: 0.00000318 AC XY: 2 AN XY: 628268

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26110

American (AMR) AF: 0.00 AC: 0 AN: 21708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18368

East Asian (EAS) AF: 0.00 AC: 0 AN: 32914

South Asian (SAS) AF: 0.00 AC: 0 AN: 62034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 9.70e-7 AC: 1 AN: 1031300

Other (OTH) AF: 0.0000188 AC: 1 AN: 53256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 4 Uncertain:1

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 394 of the KCNK3 protein (p.Val394Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 474317). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant 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	Benign	0.29
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		4.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.28
MutPred		0.28		.;Gain of solvent accessibility (P = 0.1683);
MVP		0.34
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.48
Mutation Taster		=80/20	polymorphism

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: rs1553387738; hg19: chr2-26951431;