11-17388025-T-C

Position:

• chr11-17388025-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 2.12

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]

ACMG classification

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/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.67A>G	p.Lys23Glu	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001377296.1	c.-24A>G		5_prime_UTR_variant	2/3		NP_001364225.1
KCNJ11	NM_001166290.2	c.-16-179A>G		intron_variant			NP_001159762.1
KCNJ11	NM_001377297.1	c.-16-179A>G		intron_variant			NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.67A>G	p.Lys23Glu	missense_variant	1/1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108604 AN: 152122 Hom.: 40242 Cov.: 35

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

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.: 64 AF XY: 0.640 AC XY: 465281 AN XY: 726874

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.: 35 AF XY: 0.708 AC XY: 52690 AN XY: 74440

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:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Permanent neonatal diabetes mellitus Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Hyperinsulinemic hypoglycemia, familial, 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

Type 2 diabetes mellitus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Hyperinsulinism, Dominant/Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Diabetes mellitus type 2, susceptibility to Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Dec 01, 2009

- -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

KCNJ11-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity-onset diabetes of the young type 13 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.92
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.086	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.17
Sift	Benign	0.32	T
Sift4G	Benign	0.23	T
Vest4		0.0090
MPC		0.86
ClinPred		0.0012	T
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

Other links and lift over

dbSNP: rs5219; hg19: chr11-17409572; COSMIC: COSV56858357; COSMIC: COSV56858357;