chr2-26692904-C-A

Position:

• chr2-26692904-C-A

Variant summary

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

The NM_002246.3(KCNK3):​c.29C>A​(p.Ala10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,342,294 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: KCNK3 NM_002246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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.29C>A	p.Ala10Glu	missense_variant	1/2	ENST00000302909.4	NP_002237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK3	ENST00000302909.4	c.29C>A	p.Ala10Glu	missense_variant	1/2	1	NM_002246.3	ENSP00000306275	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1342294 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 659086

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: 9.49e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 07, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 10 of the KCNK3 protein (p.Ala10Glu). 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. 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: "Deleterious"; 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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.088	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.91	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.12	T
Polyphen		0.77	P
Vest4		0.50
MVP		0.51
ClinPred		0.78	D
GERP RS		2.2
Varity_R		0.60
gMVP		0.95

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: rs1447822219; hg19: chr2-26915772;