rs151228365

chr2-26727806-C-Achr2-26727806-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002246.3(KCNK3):c.423C>A(p.His141Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00077 in 1,611,298 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011818379).
• BP6: Variant 2-26727806-C-A is Benign according to our data. Variant chr2-26727806-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 474321.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26727806-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK3	NM_002246.3	c.423C>A	p.His141Gln	missense_variant	2/2	ENST00000302909.4
KCNK3	XM_005264293.3	c.93C>A	p.His31Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK3	ENST00000302909.4	c.423C>A	p.His141Gln	missense_variant	2/2	1	NM_002246.3	P1

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152264 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000745 AC: 186 AN: 249766 Hom.: 0 AF XY: 0.000733 AC XY: 99 AN XY: 135012

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00554

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000514

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000751 AC: 1095 AN: 1458916 Hom.: 1 Cov.: 31 AF XY: 0.000746 AC XY: 541 AN XY: 725300

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00616

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000661

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152382 Hom.: 1 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74522

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000844 Hom.: 1

Bravo AF: 0.00111

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00125

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.28	T;T
Polyphen		0.040	.;B
Vest4		0.49
MutPred		0.36		.;Loss of disorder (P = 0.1492);
MVP		0.41
ClinPred		0.040	T
GERP RS		4.4
Varity_R		0.58
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: rs151228365; hg19: chr2-26950674; COSMIC: COSV57192061;