11-17387003-T-C

Variant names:

• chr11-17387003-T-C
• rs5214
• NM_000525.4:c.1089A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000525.4(KCNJ11):​c.1089A>G​(p.Ser363Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000965 in 1,613,952 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S363S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (10 hom., cov: 34)
  • Exomes 𝑓: 0.00051 (8 hom.)
• Consequence: KCNJ11 NM_000525.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -4.27
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17387003-T-C is Benign according to our data. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671. Variant chr11-17387003-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158671.
• BP7: Synonymous conserved (PhyloP=-4.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0053 (807/152338) while in subpopulation AFR AF = 0.0184 (764/41582). AF 95% confidence interval is 0.0173. There are 10 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.1089A>G	p.Ser363Ser	synonymous_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.828A>G	p.Ser276Ser	synonymous_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1	c.828A>G	p.Ser276Ser	synonymous_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1	c.828A>G	p.Ser276Ser	synonymous_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.1089A>G	p.Ser363Ser	synonymous_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1	c.828A>G	p.Ser276Ser	synonymous_variant	Exon 2 of 2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1	c.828A>G	p.Ser276Ser	synonymous_variant	Exon 2 of 2			ENSP00000508090.1
KCNJ11	ENST00000682764.1	c.828A>G	p.Ser276Ser	synonymous_variant	Exon 2 of 3			ENSP00000506780.1

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 794 AN: 152220 Hom.: 10 Cov.: 34

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 251056 AF XY: 0.000788

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000513 AC: 750 AN: 1461614 Hom.: 8 Cov.: 32 AF XY: 0.000436 AC XY: 317 AN XY: 727060

African (AFR) AF: 0.0177 AC: 592 AN: 33474

American (AMR) AF: 0.00127 AC: 57 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111828

Other (OTH) AF: 0.00141 AC: 85 AN: 60380

GnomAD4 genome AF: 0.00530 AC: 807 AN: 152338 Hom.: 10 Cov.: 34 AF XY: 0.00518 AC XY: 386 AN XY: 74502

African (AFR) AF: 0.0184 AC: 764 AN: 41582

American (AMR) AF: 0.00196 AC: 30 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00268 Hom.: 0

Bravo AF: 0.00607

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10338089) -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

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 may be responsive to oral sulfonylureas. It is also associated with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of this particular variant (rs5214) in MODY yet. -

Inborn genetic diseases Benign:1

Mar 30, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Diabetes mellitus, transient neonatal, 3 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Permanent neonatal diabetes mellitus Benign:1

Sep 25, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperinsulinemic hypoglycemia, familial, 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0080
DANN	Benign	0.63
PhyloP100		-4.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs5214; hg19: chr11-17408550;