rs5215

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000525.4(KCNJ11):c.1009G>A(p.Val337Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,613,990 control chromosomes in the GnomAD database, including 342,278 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 ( 39353 hom., cov: 34)

Exomes 𝑓: 0.64 ( 302925 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: -0.120

Publications

391 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 -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_000525.4

BP4

Computational evidence support a benign effect (MetaRNN=8.4797284E-7).

BP6

Variant 11-17387083-C-T is Benign according to our data. Variant chr11-17387083-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNJ11	NM_000525.4 link	c.1009G>A	p.Val337Ile	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2 link	c.748G>A	p.Val250Ile	missense_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1 link	c.748G>A	p.Val250Ile	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1 link	c.748G>A	p.Val250Ile	missense_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNJ11	ENST00000339994.5 link	c.1009G>A	p.Val337Ile	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1 link	c.748G>A	p.Val250Ile	missense_variant	Exon 2 of 2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1 link	c.748G>A	p.Val250Ile	missense_variant	Exon 2 of 2			ENSP00000508090.1
KCNJ11	ENST00000682764.1 link	c.748G>A	p.Val250Ile	missense_variant	Exon 2 of 3			ENSP00000506780.1

Frequencies

GnomAD3 genomes

AF:

0.708

AC:

107545

AN:

152006

Hom.:

39303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.911

Gnomad AMI

AF:

0.482

Gnomad AMR

AF:

0.670

Gnomad ASJ

AF:

0.645

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.625

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.697

Gnomad NFE

AF:

0.637

Gnomad OTH

AF:

0.687

GnomAD2 exomes

AF:

0.638

AC:

160506

AN:

251456

AF XY:

0.634

show subpopulations

Gnomad AFR exome

AF:

0.916

Gnomad AMR exome

AF:

0.618

Gnomad ASJ exome

AF:

0.637

Gnomad EAS exome

AF:

0.635

Gnomad FIN exome

AF:

0.522

Gnomad NFE exome

AF:

0.630

Gnomad OTH exome

AF:

0.635

GnomAD4 exome

AF:

0.641

AC:

937700

AN:

1461864

Hom.:

302925

Cov.:

AF XY:

0.639

AC XY:

464957

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.924

AC:

30931

AN:

33480

American (AMR)

AF:

0.623

AC:

27860

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

16749

AN:

26136

East Asian (EAS)

AF:

0.633

AC:

25142

AN:

39700

South Asian (SAS)

AF:

0.630

AC:

54339

AN:

86258

European-Finnish (FIN)

AF:

0.523

AC:

27945

AN:

53416

Middle Eastern (MID)

AF:

0.724

AC:

4174

AN:

5766

European-Non Finnish (NFE)

AF:

0.639

AC:

711073

AN:

1111988

Other (OTH)

AF:

0.654

AC:

39487

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

23154

46309

69463

92618

115772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18918

37836

56754

75672

94590

<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:

0.708

AC:

107657

AN:

152126

Hom.:

39353

Cov.:

AF XY:

0.702

AC XY:

52184

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.911

AC:

37832

AN:

41540

American (AMR)

AF:

0.670

AC:

10243

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.645

AC:

2240

AN:

3472

East Asian (EAS)

AF:

0.647

AC:

3333

AN:

5148

South Asian (SAS)

AF:

0.625

AC:

3010

AN:

4818

European-Finnish (FIN)

AF:

0.531

AC:

5619

AN:

10586

Middle Eastern (MID)

AF:

0.704

AC:

207

AN:

294

European-Non Finnish (NFE)

AF:

0.637

AC:

43283

AN:

67962

Other (OTH)

AF:

0.686

AC:

1451

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1525

3051

4576

6102

7627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<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:

0.656

Hom.:

149415

Bravo

AF:

0.722

TwinsUK

AF:

0.650

AC:

2410

ALSPAC

AF:

0.637

AC:

2456

ESP6500AA

AF:

0.913

AC:

4018

ESP6500EA

AF:

0.639

AC:

5488

ExAC

AF:

0.645

AC:

78262

Asia WGS

AF:

0.663

AC:

2305

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

- -

Jun 02, 2021

Athena Diagnostics

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

- -

not provided

Benign:3

Sep 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31118516, 30389748, 26551672, 27398621, 17257281, 22958899) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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. -

Hyperinsulinemic hypoglycemia, familial, 2

Benign:2

Jul 01, 2021

Pars Genome Lab

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

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

- -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Type 2 diabetes mellitus

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

Mutations can cause decreased production of insulin and secretion. This can lead to MODY which is responsive to oral sulfonylureas. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

8.3

(source)

DANN

Benign

0.93

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.48

T;.

MetaRNN

Benign

8.5e-7

T;T

MetaSVM

Benign

-0.82

PhyloP100

-0.12

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.27

Sift

Benign

0.15

T;T

Sift4G

Benign

0.20

T;T

Vest4

0.017

MPC

0.51

ClinPred

0.0052

GERP RS

-6.0

gMVP

0.22

Mutation Taster

=97/3

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