11-17388025-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000525.4(KCNJ11):c.67A>G(p.Lys23Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,613,446 control chromosomes in the GnomAD database, including 344,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.71 ( 40302 hom., cov: 35)

Exomes 𝑓: 0.64 ( 303818 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 2.12

Publications

713 publications found

Variant links:

Genes affected

KCNJ11 (HGNC:6257): (potassium inwardly rectifying channel subfamily J member 11) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor SUR. Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM), transient neonatal diabetes mellitus type 3 (TNDM3), and permanent neonatal diabetes mellitus (PNDM). Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2009]

KCNJ11 Gene-Disease associations (from GenCC):

diabetes mellitus, transient neonatal, 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hyperinsulinemic hypoglycemia, familial, 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
diabetes mellitus, permanent neonatal 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young type 13
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant hyperinsulinism due to Kir6.2 deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
DEND syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate DEND syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
permanent neonatal diabetes mellitus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
transient neonatal diabetes mellitus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hyperinsulinism due to Kir6.2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KCNJ11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.8824744E-7).

BP6

Variant 11-17388025-T-C is Benign according to our data. Variant chr11-17388025-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNJ11	NM_000525.4 link	c.67A>G	p.Lys23Glu	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001377296.1 link	c.-24A>G		5_prime_UTR_variant	Exon 2 of 3		NP_001364225.1
KCNJ11	NM_001166290.2 link	c.-16-179A>G		intron_variant	Intron 1 of 1		NP_001159762.1
KCNJ11	NM_001377297.1 link	c.-16-179A>G		intron_variant	Intron 1 of 1		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5 link	c.67A>G	p.Lys23Glu	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes

AF:

0.714

AC:

108604

AN:

152122

Hom.:

40242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.933

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.672

Gnomad ASJ

AF:

0.646

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.627

Gnomad FIN

AF:

0.532

Gnomad MID

AF:

0.701

Gnomad NFE

AF:

0.637

Gnomad OTH

AF:

0.692

GnomAD2 exomes

AF:

0.640

AC:

160417

AN:

250574

AF XY:

0.635

show subpopulations

Gnomad AFR exome

AF:

0.938

Gnomad AMR exome

AF:

0.619

Gnomad ASJ exome

AF:

0.637

Gnomad EAS exome

AF:

0.635

Gnomad FIN exome

AF:

0.523

Gnomad NFE exome

AF:

0.630

Gnomad OTH exome

AF:

0.635

GnomAD4 exome

AF:

0.642

AC:

938548

AN:

1461206

Hom.:

303818

Cov.:

AF XY:

0.640

AC XY:

465281

AN XY:

726874

show subpopulations

African (AFR)

AF:

0.946

AC:

31681

AN:

33480

American (AMR)

AF:

0.625

AC:

27924

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

16748

AN:

26134

East Asian (EAS)

AF:

0.634

AC:

25146

AN:

39692

South Asian (SAS)

AF:

0.631

AC:

54393

AN:

86252

European-Finnish (FIN)

AF:

0.524

AC:

27779

AN:

52992

Middle Eastern (MID)

AF:

0.725

AC:

4180

AN:

5768

European-Non Finnish (NFE)

AF:

0.640

AC:

711099

AN:

1111794

Other (OTH)

AF:

0.656

AC:

39598

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20879

41758

62637

83516

104395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18920

37840

56760

75680

94600

<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:

0.714

AC:

108727

AN:

152240

Hom.:

40302

Cov.:

AF XY:

0.708

AC XY:

52690

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.933

AC:

38784

AN:

41556

American (AMR)

AF:

0.672

AC:

10285

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.646

AC:

2239

AN:

3468

East Asian (EAS)

AF:

0.646

AC:

3332

AN:

5158

South Asian (SAS)

AF:

0.626

AC:

3025

AN:

4830

European-Finnish (FIN)

AF:

0.532

AC:

5639

AN:

10602

Middle Eastern (MID)

AF:

0.705

AC:

206

AN:

292

European-Non Finnish (NFE)

AF:

0.637

AC:

43315

AN:

68000

Other (OTH)

AF:

0.690

AC:

1461

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1556

3112

4669

6225

7781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.659

Hom.:

147614

Bravo

AF:

0.730

TwinsUK

AF:

0.650

AC:

2409

ALSPAC

AF:

0.638

AC:

2457

ESP6500AA

AF:

0.931

AC:

4095

ESP6500EA

AF:

0.639

AC:

5490

ExAC

AF:

0.647

AC:

78506

Asia WGS

AF:

0.667

AC:

2321

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28252621, 15111507, 25625107, 25165692, 24332549, 31118516, 29632382, 28082085, 25725792, 27535653, 25955821, 24996284, 26551672, 27398621, 26315042, 9867219, 24741969, 16733889, 24710510, 22163043, 22209866, 24241377, 22264780, 23054005, 23412854, 19498446, 17823772, 19578796, 19685080, 19214942, 22082043, 19491206, 15855351, 12196481, 20424228, 19587354, 17257281, 16455067, 19233137, 22704848, 18758683) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Permanent neonatal diabetes mellitus

Benign:2Other:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 26, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperinsulinemic hypoglycemia, familial, 2

Benign:2

Apr 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Type 2 diabetes mellitus

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which is responsive to oral sulfonylureas. KCNJ11 rs5219- E23K is associated with Type II Diabetes Mellitus. It doesnt cause any sensitivity towards mild hypoglycemia, an adverse effect of Sulfonylurea treatment. -

Diabetes mellitus, transient neonatal, 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hyperinsulinism, Dominant/Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diabetes mellitus type 2, susceptibility to

Benign:1

Dec 01, 2009

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Maturity onset diabetes mellitus in young

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KCNJ11-related disorder

Benign:1

Apr 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Transient Neonatal Diabetes, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity-onset diabetes of the young type 13

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.92

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.086

MetaRNN

Benign

6.9e-7

MetaSVM

Benign

-0.97

PhyloP100

2.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.32

REVEL

Benign

0.17

Sift

Benign

0.32

Sift4G

Benign

0.23

Vest4

0.0090

MPC

0.86

ClinPred

0.0012

GERP RS

4.3

gMVP

0.51

Mutation Taster

=95/5

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over