Genetic Variant NM_001135106.2:c.830C>A (chr6-39316274-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001135106.2(KCNK16):c.830C>A(p.Ala277Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,587,940 control chromosomes in the GnomAD database, including 210,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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 0.59 ( 28607 hom., cov: 32)

Exomes 𝑓: 0.50 ( 182072 hom. )

Consequence

KCNK16
NM_001135106.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.231

Publications

107 publications found

Variant links:

Genes affected

KCNK16 (HGNC:14464): (potassium two pore domain channel subfamily K member 16) 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 expressed predominantly in the pancreas and is activated at alkaline pH. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Sep 2008]

KCNK16 links:

LOC105375047 (HGNC:):

LOC105375047 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2058849E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK16	NM_001135106.2 link	c.830C>A	p.Ala277Glu	missense_variant	Exon 5 of 5	ENST00000437525.3	NP_001128578.1	Q96T55-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK16	ENST00000437525.3 link	c.830C>A	p.Ala277Glu	missense_variant	Exon 5 of 5	1	NM_001135106.2	ENSP00000415375.2		Q96T55-3

Frequencies

GnomAD3 genomes

AF:

0.593

AC:

90070

AN:

151914

Hom.:

28565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.837

Gnomad AMI

AF:

0.555

Gnomad AMR

AF:

0.515

Gnomad ASJ

AF:

0.569

Gnomad EAS

AF:

0.462

Gnomad SAS

AF:

0.503

Gnomad FIN

AF:

0.502

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.493

Gnomad OTH

AF:

0.605

GnomAD2 exomes

AF:

0.505

AC:

102644

AN:

203114

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.850

Gnomad AMR exome

AF:

0.433

Gnomad ASJ exome

AF:

0.552

Gnomad EAS exome

AF:

0.465

Gnomad FIN exome

AF:

0.502

Gnomad NFE exome

AF:

0.488

Gnomad OTH exome

AF:

0.535

GnomAD4 exome

AF:

0.499

AC:

716971

AN:

1435908

Hom.:

182072

Cov.:

AF XY:

0.499

AC XY:

355070

AN XY:

711544

show subpopulations

African (AFR)

AF:

0.857

AC:

28402

AN:

33140

American (AMR)

AF:

0.446

AC:

18085

AN:

40570

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14143

AN:

25536

East Asian (EAS)

AF:

0.410

AC:

15894

AN:

38754

South Asian (SAS)

AF:

0.497

AC:

40847

AN:

82216

European-Finnish (FIN)

AF:

0.503

AC:

25642

AN:

50958

Middle Eastern (MID)

AF:

0.617

AC:

3293

AN:

5338

European-Non Finnish (NFE)

AF:

0.490

AC:

539099

AN:

1099966

Other (OTH)

AF:

0.531

AC:

31566

AN:

59430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

19359

38718

58078

77437

96796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15932

31864

47796

63728

79660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.593

AC:

90155

AN:

152032

Hom.:

28607

Cov.:

AF XY:

0.592

AC XY:

43996

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.837

AC:

34717

AN:

41486

American (AMR)

AF:

0.515

AC:

7874

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.569

AC:

1975

AN:

3472

East Asian (EAS)

AF:

0.462

AC:

2371

AN:

5134

South Asian (SAS)

AF:

0.502

AC:

2409

AN:

4800

European-Finnish (FIN)

AF:

0.502

AC:

5324

AN:

10596

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.493

AC:

33529

AN:

67942

Other (OTH)

AF:

0.600

AC:

1259

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1723

3446

5169

6892

8615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.542

Hom.:

12918

Bravo

AF:

0.607

TwinsUK

AF:

0.491

AC:

1820

ALSPAC

AF:

0.482

AC:

1858

ESP6500AA

AF:

0.833

AC:

3645

ESP6500EA

AF:

0.500

AC:

4293

ExAC

AF:

0.484

AC:

57757

Asia WGS

AF:

0.540

AC:

1874

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.39

(source)

DANN

Benign

0.60

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-0.97

PhyloP100

-0.23

PROVEAN

Benign

0.0

REVEL

Benign

0.0080

Sift

Benign

0.11

Sift4G

Uncertain

0.051

Vest4

0.050

ClinPred

0.0029

GERP RS

1.9

Mutation Taster

=93/7

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over