6-39303993-T-C

Variant names:

• chr6-39303993-T-C
• rs943061480
• NM_031460.4:c.652A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031460.4(KCNK17):​c.652A>G​(p.Thr218Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNK17 NM_031460.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53
• Publications: 0 publications found

Genes affected

KCNK17 (HGNC:14465): (potassium two pore domain channel subfamily K member 17) The protein encoded by this gene belongs to the family of potassium channel proteins containing two pore-forming P domains. This channel is an open rectifier which primarily passes outward current under physiological K+ concentrations. This gene is activated at alkaline pH. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

KCNK17 Gene-Disease associations (from GenCC):

• heart conduction disease

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK17	NM_031460.4	c.652A>G	p.Thr218Ala	missense_variant	Exon 4 of 5	ENST00000373231.9	NP_113648.2
KCNK17	NM_001135111.2	c.652A>G	p.Thr218Ala	missense_variant	Exon 4 of 6		NP_001128583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK17	ENST00000373231.9	c.652A>G	p.Thr218Ala	missense_variant	Exon 4 of 5	1	NM_031460.4	ENSP00000362328.4
KCNK17	ENST00000503878.1	n.1120A>G		non_coding_transcript_exon_variant	Exon 3 of 3	1
KCNK17	ENST00000453413.2	c.652A>G	p.Thr218Ala	missense_variant	Exon 4 of 6	5		ENSP00000401271.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.652A>G (p.T218A) alteration is located in exon 4 (coding exon 4) of the KCNK17 gene. This alteration results from a A to G substitution at nucleotide position 652, causing the threonine (T) at amino acid position 218 to be replaced by an alanine (A). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		5.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.77		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.83
MPC		0.81
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.75
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs943061480; hg19: chr6-39271769;