1-215169219-C-G

Variant names:

• chr1-215169219-C-G
• rs576428312
• NM_001017425.3:c.496C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001017425.3(KCNK2):​c.496C>G​(p.Arg166Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,218 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNK2 NM_001017425.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• Publications: 5 publications found

Genes affected

KCNK2 (HGNC:6277): (potassium two pore domain channel subfamily K member 2) This gene encodes one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK2	NM_001017425.3	c.496C>G	p.Arg166Gly	missense_variant	Exon 4 of 7	ENST00000444842.7	NP_001017425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK2	ENST00000444842.7	c.496C>G	p.Arg166Gly	missense_variant	Exon 4 of 7	1	NM_001017425.3	ENSP00000394033.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455218 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723706

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 43392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 84680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109350

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	.;.;.;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;D;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;.;L;.
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.087	T;T;T;T;T
Sift4G	Benign	0.097	T;T;.;T;T
Polyphen		0.71	P;.;B;P;.
Vest4		0.59
MutPred		0.65		.;.;.;Gain of disorder (P = 0.0939);.;
MVP		0.52
MPC		1.0
ClinPred		0.91	D
GERP RS		6.2
Varity_R		0.59
gMVP		0.75
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs576428312; hg19: chr1-215342562;