rs398123041

Positions:

• chr2-26728044-G-A
• chr2-26728044-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002246.3(KCNK3):​c.661G>A​(p.Val221Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,340 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.83

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK3	NM_002246.3	c.661G>A	p.Val221Met	missense_variant	2/2	ENST00000302909.4	NP_002237.1
KCNK3	XM_005264293.3	c.331G>A	p.Val111Met	missense_variant	2/2		XP_005264350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK3	ENST00000302909.4	c.661G>A	p.Val221Met	missense_variant	2/2	1	NM_002246.3	ENSP00000306275.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.47		.;Gain of sheet (P = 0.0477);
MVP		0.56
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.93

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: rs398123041; hg19: chr2-26950912; COSMIC: COSV100257283;