rs1553387738

Positions:

• chr2-26728563-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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 Uncertain_significance. Variant got 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/exons	MANE	UniProt
KCNK3	NM_002246.3	c.1180G>A	p.Val394Met	missense_variant	2/2	ENST00000302909.4
KCNK3	XM_005264293.3	c.850G>A	p.Val284Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK3	ENST00000302909.4	c.1180G>A	p.Val394Met	missense_variant	2/2	1	NM_002246.3	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.70e-7

Gnomad4 OTH exome AF: 0.0000188

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

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
MutationTaster	Benign	0.56	N
PrimateAI	Pathogenic	0.87	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

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: rs1553387738; hg19: chr2-26951431;