Genetic Variant KCNK17:p.Tyr308Cys (chr6-39299503-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_031460.4(KCNK17):c.923A>G(p.Tyr308Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000865 in 1,614,214 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 2 hom. )

Consequence

KCNK17
NM_031460.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.93

Publications

5 publications found

Variant links:

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

KCNK17 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009340227).

BS2

High Homozygotes in GnomAdExome4 at 2 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK17	NM_031460.4 link	c.923A>G	p.Tyr308Cys	missense_variant	Exon 5 of 5	ENST00000373231.9	NP_113648.2	Q96T54-3
KCNK17	NM_001135111.2 link	c.*258A>G		3_prime_UTR_variant	Exon 6 of 6		NP_001128583.1	Q96T54-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK17	ENST00000373231.9 link	c.923A>G	p.Tyr308Cys	missense_variant	Exon 5 of 5	1	NM_031460.4	ENSP00000362328.4		Q96T54-3
KCNK17	ENST00000453413.2 link	c.*258A>G		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000401271.2		Q96T54-4

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000489

AC:

123

AN:

251396

AF XY:

0.000574

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000914

AC:

1336

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000869

AC XY:

632

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00116

AC:

1291

AN:

1112012

Other (OTH)

AF:

0.000580

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000394

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000749

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.923A>G (p.Y308C) alteration is located in exon 5 (coding exon 5) of the KCNK17 gene. This alteration results from a A to G substitution at nucleotide position 923, causing the tyrosine (Y) at amino acid position 308 to be replaced by a cysteine (C). 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

0.060

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0060

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.013

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.43

M_CAP

Benign

0.0015

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PhyloP100

-2.9

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.57

REVEL

Benign

0.0040

Sift

Benign

0.19

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.089

MVP

0.14

MPC

0.27

ClinPred

0.0055

GERP RS

-9.0

Varity_R

0.029

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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chr6-39299503-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over