rs201264306

Positions:

chr11-17387566-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000525.4(KCNJ11):c.526C>T(p.Arg176Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,613,088 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.83

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000525.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNJ11	NM_000525.4 linkuse as main transcript	c.526C>T	p.Arg176Cys	missense_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2 linkuse as main transcript	c.265C>T	p.Arg89Cys	missense_variant	2/2
KCNJ11	NM_001377296.1 linkuse as main transcript	c.265C>T	p.Arg89Cys	missense_variant	3/3
KCNJ11	NM_001377297.1 linkuse as main transcript	c.265C>T	p.Arg89Cys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5 linkuse as main transcript	c.526C>T	p.Arg176Cys	missense_variant	1/1		NM_000525.4	P1	Q14654-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248678

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134600

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1460914

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726764

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000570

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000777

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

KCNJ11-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2023

The KCNJ11 c.526C>T variant is predicted to result in the amino acid substitution p.Arg176Cys. This variant has been reported in individuals with diabetes but did not segregate with disease within the family (Edghill EL et al 2004. PubMed ID: 15504982; Flechtner et al 2006. PubMed ID: 17296510). Functional studies using artificial mutation showed that this variant may affect KCNJ11 function (John SA et al 2001. PubMed ID: 11585851). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17409113-G-A). This variant is classified as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/211223/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 176 of the KCNJ11 protein (p.Arg176Cys). This variant is present in population databases (rs201264306, gnomAD 0.009%). This missense change has been observed in individual(s) with diabetes mellitus (PMID: 15504982). ClinVar contains an entry for this variant (Variation ID: 211223). 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: 11585851). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Maturity-onset diabetes of the young type 13

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 04, 2022

_x000D_ Criteria applied: PM5_STR, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;.;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;.

Vest4

0.75

MVP

0.99

MPC

1.9

ClinPred

0.97

GERP RS

5.2

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