11-17387103-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000525.4(KCNJ11):c.989A>G(p.Tyr330Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y330H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.02

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

diabetes mellitus, transient neonatal, 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hyperinsulinemic hypoglycemia, familial, 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
diabetes mellitus, permanent neonatal 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young type 13
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant hyperinsulinism due to Kir6.2 deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
DEND syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate DEND syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
permanent neonatal diabetes mellitus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
transient neonatal diabetes mellitus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hyperinsulinism due to Kir6.2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KCNJ11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000525.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17387104-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158688.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 11-17387103-T-C is Pathogenic according to our data. Variant chr11-17387103-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNJ11	NM_000525.4 link	c.989A>G	p.Tyr330Cys	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2 link	c.728A>G	p.Tyr243Cys	missense_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1 link	c.728A>G	p.Tyr243Cys	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1 link	c.728A>G	p.Tyr243Cys	missense_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNJ11	ENST00000339994.5 link	c.989A>G	p.Tyr330Cys	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1 link	c.728A>G	p.Tyr243Cys	missense_variant	Exon 2 of 2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1 link	c.728A>G	p.Tyr243Cys	missense_variant	Exon 2 of 2			ENSP00000508090.1
KCNJ11	ENST00000682764.1 link	c.728A>G	p.Tyr243Cys	missense_variant	Exon 2 of 3			ENSP00000506780.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus

Pathogenic:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely pathogenic

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. rs193929356 (c.989A>G, p.Y330C) of KCNJ11 is associated with early onset Type I Diabetes Mellitus. -

Neonatal insulin-dependent diabetes mellitus

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jun 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 21204). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with early onset diabetes (PMID: 15448107, 29361385, 32792356). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the KCNJ11 protein (p.Tyr330Cys). -

Permanent neonatal diabetes mellitus

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

PhyloP100

8.0

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.1

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.94

MutPred

0.96

Loss of phosphorylation at Y330 (P = 0.0437);.;

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

5.4

gMVP

0.88

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over