rs150626749

chr2-26728336-G-Achr2-26728336-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002246.3(KCNK3):c.953G>A(p.Arg318His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,604,142 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.50

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070228577).
• BP6: Variant 2-26728336-G-A is Benign according to our data. Variant chr2-26728336-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569441.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK3	NM_002246.3	c.953G>A	p.Arg318His	missense_variant	2/2	ENST00000302909.4
KCNK3	XM_005264293.3	c.623G>A	p.Arg208His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK3	ENST00000302909.4	c.953G>A	p.Arg318His	missense_variant	2/2	1	NM_002246.3	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000334 AC: 75 AN: 224280 Hom.: 0 AF XY: 0.000294 AC XY: 36 AN XY: 122466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00709

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000198 AC: 287 AN: 1451940 Hom.: 2 Cov.: 31 AF XY: 0.000197 AC XY: 142 AN XY: 721460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00760

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000460

Gnomad4 OTH exome AF: 0.000650

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000281 AC: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pulmonary hypertension, primary, 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.953G>A (p.R318H) alteration is located in exon 2 (coding exon 2) of the KCNK3 gene. This alteration results from a G to A substitution at nucleotide position 953, causing the arginine (R) at amino acid position 318 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.60	D
PrimateAI	Uncertain	0.74	T
Sift4G	Benign	0.45	T;T
Polyphen		0.037	.;B
Vest4		0.11
MVP		0.33
ClinPred		0.065	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.70

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: rs150626749; hg19: chr2-26951204;