11-17388025-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 67) in uniprot entity KCJ11_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000525.4

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 [Likely_benign]. Clinvar id is 8678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17388025-T-C is described in Lovd as [Benign].

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	UniProt
KCNJ11	NM_000525.4 link	c.67A>G	p.Lys23Glu	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3	Q14654-1B2RC52
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	Q14654-2A0A804HHV7
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		Q14654-1

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

GnomAD3 exomes

AF:

0.640

AC:

160417

AN:

250574

Hom.:

52327

AF XY:

0.635

AC XY:

86123

AN XY:

135542

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 SAS exome

AF:

0.629

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

Gnomad4 AFR exome

AF:

0.946

Gnomad4 AMR exome

AF:

0.625

Gnomad4 ASJ exome

AF:

0.641

Gnomad4 EAS exome

AF:

0.634

Gnomad4 SAS exome

AF:

0.631

Gnomad4 FIN exome

AF:

0.524

Gnomad4 NFE exome

AF:

0.640

Gnomad4 OTH exome

AF:

0.656

GnomAD4 genome

AF:

0.714

AC:

108727

AN:

152240

Hom.:

40302

Cov.:

AF XY:

0.708

AC XY:

52690

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.933

Gnomad4 AMR

AF:

0.672

Gnomad4 ASJ

AF:

0.646

Gnomad4 EAS

AF:

0.646

Gnomad4 SAS

AF:

0.626

Gnomad4 FIN

AF:

0.532

Gnomad4 NFE

AF:

0.637

Gnomad4 OTH

AF:

0.690

Alfa

AF:

0.645

Hom.:

73092

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

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Permanent neonatal diabetes mellitus

Benign:2Other:1

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

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2014

Eurofins Ntd Llc (ga)

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. -

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

- -

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

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

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

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over