rs587783672

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000525.4(KCNJ11):c.679G>A(p.Glu227Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7B:1

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 11-17387413-C-T is Pathogenic according to our data. Variant chr11-17387413-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4 link	c.679G>A	p.Glu227Lys	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3	Q14654-1B2RC52
KCNJ11	NM_001166290.2 link	c.418G>A	p.Glu140Lys	missense_variant	Exon 2 of 2		NP_001159762.1	Q14654-2A0A804HHV7
KCNJ11	NM_001377296.1 link	c.418G>A	p.Glu140Lys	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1 link	c.418G>A	p.Glu140Lys	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.679G>A	p.Glu227Lys	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4		Q14654-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250756

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes mellitus

Pathogenic:2

Jul 23, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

PS1 PM1 PM2 PP2 PP3 -

not provided

Pathogenic:2

Apr 04, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been seen in multiple individuals with autosomal dominant neonatal diabetes (PMID: 4622368, 32893419, 32101525, 35114785, 35612844). It has been observed to segregate with disease within multiple unrelated families (PMID: 17327377, 17490422, 22471336) and identified as de novo in several individuals (PMID: 17327377, 33538814, 37664823). Additionally, it has been observed in individuals with later onset diabetes without confirmed history of neonatal diabetes (PMID: 32101525, 22701567, 33538814). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17021801) -

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 227 of the KCNJ11 protein (p.Glu227Lys). This variant is present in population databases (rs587783672, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant KCNJ11-related early onset diabetes (PMID: 2270156, 2462236). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158682). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 17021801). For these reasons, this variant has been classified as Pathogenic. -

Neonatal diabetes mellitus

Pathogenic:1

Molecular Genetics, Madras Diabetes Research Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diabetes mellitus, transient neonatal, 3

Pathogenic:1

Jan 17, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Maturity-onset diabetes of the young type 13

Pathogenic:1

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: flagged submission

Collection Method: research

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. rs587783672(p.Glu227Lys) can lead to MODY which may be responsive to oral sulfonylureas. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0020

D;D;.

Vest4

0.77

MutPred

0.95

Gain of ubiquitination at E227 (P = 0.0131);.;.;

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

5.3

gMVP

0.96

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