Genetic Variant KCNK10:p.Ala517Thr (chr14-88185618-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138317.3(KCNK10):c.1549G>A(p.Ala517Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,613,932 control chromosomes in the GnomAD database, including 53,615 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3843 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49772 hom. )

Consequence

KCNK10
NM_138317.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.95

Variant links:

Genes affected

KCNK10 (HGNC:6273): (potassium two pore domain channel subfamily K member 10) 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, and is stimulated strongly by arachidonic acid and to a lesser degree by membrane stretching, intracellular acidification, and general anaesthetics. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Sep 2008]

KCNK10 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039073527).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK10	NM_138317.3 link	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7	ENST00000319231.10	NP_612190.1	P57789-3
KCNK10	NM_138318.3 link	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7		NP_612191.1	P57789-4
KCNK10	NM_021161.5 link	c.1534G>A	p.Ala512Thr	missense_variant	Exon 7 of 7		NP_066984.1	P57789-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNK10	ENST00000319231.10 link	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7	1	NM_138317.3	ENSP00000312811.5	P57789-3
KCNK10	ENST00000312350.9 link	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7	1		ENSP00000310568.5	P57789-4
KCNK10	ENST00000340700.9 link	c.1534G>A	p.Ala512Thr	missense_variant	Exon 7 of 7	1		ENSP00000343104.5	P57789-1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29849

AN:

152030

Hom.:

3844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0576

Gnomad AMI

AF:

0.336

Gnomad AMR

AF:

0.165

Gnomad ASJ

AF:

0.286

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0961

Gnomad FIN

AF:

0.315

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.190

GnomAD3 exomes

AF:

0.205

AC:

51519

AN:

251264

Hom.:

6717

AF XY:

0.208

AC XY:

28296

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.0512

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.273

Gnomad EAS exome

AF:

0.0170

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.238

GnomAD4 exome

AF:

0.250

AC:

365890

AN:

1461784

Hom.:

49772

Cov.:

AF XY:

0.248

AC XY:

180093

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0498

Gnomad4 AMR exome

AF:

0.120

Gnomad4 ASJ exome

AF:

0.271

Gnomad4 EAS exome

AF:

0.0104

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.316

Gnomad4 NFE exome

AF:

0.279

Gnomad4 OTH exome

AF:

0.232

GnomAD4 genome

AF:

0.196

AC:

29837

AN:

152148

Hom.:

3843

Cov.:

AF XY:

0.197

AC XY:

14662

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0574

Gnomad4 AMR

AF:

0.164

Gnomad4 ASJ

AF:

0.286

Gnomad4 EAS

AF:

0.0162

Gnomad4 SAS

AF:

0.0963

Gnomad4 FIN

AF:

0.315

Gnomad4 NFE

AF:

0.284

Gnomad4 OTH

AF:

0.188

Alfa

AF:

0.255

Hom.:

8325

Bravo

AF:

0.178

TwinsUK

AF:

0.267

AC:

991

ALSPAC

AF:

0.263

AC:

1015

ESP6500AA

AF:

0.0647

AC:

285

ESP6500EA

AF:

0.277

AC:

2382

ExAC

AF:

0.207

AC:

25104

Asia WGS

AF:

0.0640

AC:

225

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

9.9

DANN

Benign

0.97

DEOGEN2

Benign

0.0044

T;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.11

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.84

T;T;T

Polyphen

0.043

B;.;.

Vest4

0.045

MPC

0.40

ClinPred

0.0061

GERP RS

3.5

Varity_R

0.056

gMVP

0.081

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over