NM_000525.4:c.808C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000525.4(KCNJ11):c.808C>G(p.Leu270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,614,186 control chromosomes in the GnomAD database, including 1,728 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L270M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.037 ( 175 hom., cov: 33)

Exomes 𝑓: 0.041 ( 1553 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18

Conservation

PhyloP100: 1.14

Publications

42 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001799047).

BP6

Variant 11-17387284-G-C is Benign according to our data. Variant chr11-17387284-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158685.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0373 (5683/152306) while in subpopulation NFE AF = 0.0452 (3072/68022). AF 95% confidence interval is 0.0438. There are 175 homozygotes in GnomAd4. There are 2957 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 175 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4 link	c.808C>G	p.Leu270Val	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3	Q14654-1B2RC52
KCNJ11	NM_001166290.2 link	c.547C>G	p.Leu183Val	missense_variant	Exon 2 of 2		NP_001159762.1	Q14654-2A0A804HHV7
KCNJ11	NM_001377296.1 link	c.547C>G	p.Leu183Val	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1 link	c.547C>G	p.Leu183Val	missense_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5 link	c.808C>G	p.Leu270Val	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4		Q14654-1

Frequencies

GnomAD3 genomes

AF:

0.0373

AC:

5683

AN:

152188

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00796

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0414

Gnomad ASJ

AF:

0.0599

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0522

GnomAD2 exomes

AF:

0.0405

AC:

10167

AN:

251334

AF XY:

0.0407

show subpopulations

Gnomad AFR exome

AF:

0.00640

Gnomad AMR exome

AF:

0.0298

Gnomad ASJ exome

AF:

0.0678

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.0462

Gnomad OTH exome

AF:

0.0538

GnomAD4 exome

AF:

0.0405

AC:

59210

AN:

1461880

Hom.:

1553

Cov.:

AF XY:

0.0402

AC XY:

29248

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00660

AC:

221

AN:

33480

American (AMR)

AF:

0.0301

AC:

1348

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0613

AC:

1603

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0109

AC:

942

AN:

86256

European-Finnish (FIN)

AF:

0.108

AC:

5747

AN:

53414

Middle Eastern (MID)

AF:

0.0411

AC:

237

AN:

5768

European-Non Finnish (NFE)

AF:

0.0419

AC:

46623

AN:

1112008

Other (OTH)

AF:

0.0412

AC:

2488

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3765

7530

11296

15061

18826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1642

3284

4926

6568

8210

<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:

0.0373

AC:

5683

AN:

152306

Hom.:

175

Cov.:

AF XY:

0.0397

AC XY:

2957

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00791

AC:

329

AN:

41578

American (AMR)

AF:

0.0413

AC:

632

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

208

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00807

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.114

AC:

1212

AN:

10608

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3072

AN:

68022

Other (OTH)

AF:

0.0521

AC:

110

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

274

547

821

1094

1368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0294

Hom.:

Bravo

AF:

0.0316

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.00705

AC:

ESP6500EA

AF:

0.0469

AC:

403

ExAC

AF:

0.0374

AC:

4537

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0496

EpiControl

AF:

0.0533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 25, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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: 25972930) -

Hyperinsulinemic hypoglycemia, familial, 2

Benign:3

May 19, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Diabetes mellitus, transient neonatal, 3

Benign:2

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Maturity onset diabetes mellitus in young

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in the KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which is responsive to oral sulfonylureas. However, the variant rs1800467 might not pose increased sensitivity to Type II Diabetes by itself but in combination with other variants in KCNJ11 or INS and HNF1A increase predisposition to insulin resistance. -

Diabetes mellitus, permanent neonatal 2

Benign:1

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Feb 22, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BA1 (4% overall MAF in gnomAD, 11% MAF in EF, 6.8% in AJ), BS2 (936 cases and 916 controls in T2DM): benign (Revel score 0.344 + PP3 (4 predictors) + BP4 (5 predictors): conflicing evidence, not using; no longer using BP6) -

Permanent neonatal diabetes mellitus

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Maturity-onset diabetes of the young type 13

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

D;.

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.31

PhyloP100

1.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.90

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.088

T;T

Sift4G

Benign

0.42

T;T

Vest4

0.044

MPC

0.63

ClinPred

0.0024

GERP RS

5.4

gMVP

0.54

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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