rs1800467

chr11-17387284-G-Cchr11-17387284-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.037 (175 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1553 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: 1.14

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 -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 id is 158685.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Likely_benign=1, Uncertain_significance=1}. Variant chr11-17387284-G-C is described in Lovd as [Benign]. Variant chr11-17387284-G-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 174 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ11	NM_000525.4	c.808C>G	p.Leu270Val	missense_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2	c.547C>G	p.Leu183Val	missense_variant	2/2
KCNJ11	NM_001377296.1	c.547C>G	p.Leu183Val	missense_variant	3/3
KCNJ11	NM_001377297.1	c.547C>G	p.Leu183Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5	c.808C>G	p.Leu270Val	missense_variant	1/1		NM_000525.4	P1
KCNJ11	ENST00000528731.1	c.547C>G	p.Leu183Val	missense_variant	2/2	1
KCNJ11	ENST00000682350.1	c.547C>G	p.Leu183Val	missense_variant	2/2
KCNJ11	ENST00000682764.1	c.547C>G	p.Leu183Val	missense_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5683 AN: 152188 Hom.: 174 Cov.: 33

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

GnomAD3 exomes AF: 0.0405 AC: 10167 AN: 251334 Hom.: 337 AF XY: 0.0407 AC XY: 5530 AN XY: 135852

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 SAS exome AF: 0.00947

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.: 69 AF XY: 0.0402 AC XY: 29248 AN XY: 727242

Gnomad4 AFR exome AF: 0.00660

Gnomad4 AMR exome AF: 0.0301

Gnomad4 ASJ exome AF: 0.0613

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0373 AC: 5683 AN: 152306 Hom.: 175 Cov.: 33 AF XY: 0.0397 AC XY: 2957 AN XY: 74466

Gnomad4 AFR AF: 0.00791

Gnomad4 AMR AF: 0.0413

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0294 Hom.: 33

Bravo AF: 0.0316

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0376 AC: 145

ESP6500AA AF: 0.00705 AC: 31

ESP6500EA AF: 0.0469 AC: 403

ExAC AF: 0.0374 AC: 4537

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0496

EpiControl AF: 0.0533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2016	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	This variant is associated with the following publications: (PMID: 25972930) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hyperinsulinemic hypoglycemia, familial, 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Diabetes mellitus, transient neonatal, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 22, 2019

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	18
Dann	Benign	0.95
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;.
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.46	T
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	T
GERP RS		5.4
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs1800467; hg19: chr11-17408831; COSMIC: COSV60594359; COSMIC: COSV60594359;