NM_001017425.3:c.161T>C

Variant names:

• chr1-215086482-T-C
• NM_001017425.3:c.161T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017425.3(KCNK2):​c.161T>C​(p.Ile54Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNK2 NM_001017425.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1450932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK2	NM_001017425.3	c.161T>C	p.Ile54Thr	missense_variant	Exon 2 of 7	ENST00000444842.7	NP_001017425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK2	ENST00000444842.7	c.161T>C	p.Ile54Thr	missense_variant	Exon 2 of 7	1	NM_001017425.3	ENSP00000394033.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161T>C (p.I54T) alteration is located in exon 2 (coding exon 2) of the KCNK2 gene. This alteration results from a T to C substitution at nucleotide position 161, causing the isoleucine (I) at amino acid position 54 to be replaced by a threonine (T). 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	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.13	.;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.00080
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	.;.;N
PhyloP100		4.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.19	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.51	T;T;T
Sift4G	Benign	0.44	T;.;T
Polyphen		0.0010	B;B;B
Vest4		0.34
MutPred		0.55		.;.;Gain of disorder (P = 0.0126);
MVP		0.31
MPC		0.81
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.30
gMVP		0.66
Mutation Taster		=76/24	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

hg19: chr1-215259825;