11-17386478-A-G

Position:

chr11-17386478-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000525.4(KCNJ11):c.*441T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 170,132 control chromosomes in the GnomAD database, including 16,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.43 ( 15103 hom., cov: 33)

Exomes 𝑓: 0.34 ( 1139 hom. )

Consequence

KCNJ11
NM_000525.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:4

Conservation

PhyloP100: -0.804

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:

KCNJ11 (HGNC:):

KCNJ11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4 linkuse as main transcript	c.*441T>C	3_prime_UTR_variant	1/1	ENST00000339994.5	NP_000516.3	Q14654-1B2RC52
KCNJ11	NM_001166290.2 linkuse as main transcript	c.*441T>C	3_prime_UTR_variant	2/2		NP_001159762.1	Q14654-2A0A804HHV7
KCNJ11	NM_001377296.1 linkuse as main transcript	c.*441T>C	3_prime_UTR_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1 linkuse as main transcript	c.*441T>C	3_prime_UTR_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994 linkuse as main transcript	c.*441T>C		3_prime_UTR_variant	1/1		NM_000525.4	ENSP00000345708.4		Q14654-1

Frequencies

GnomAD3 genomes

AF:

0.434

AC:

65930

AN:

151940

Hom.:

15066

Cov.:

show subpopulations

Gnomad AFR

AF:

0.570

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.391

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.399

GnomAD4 exome

AF:

0.337

AC:

6085

AN:

18072

Hom.:

1139

Cov.:

AF XY:

0.340

AC XY:

3161

AN XY:

9310

show subpopulations

Gnomad4 AFR exome

AF:

0.506

Gnomad4 AMR exome

AF:

0.333

Gnomad4 ASJ exome

AF:

0.265

Gnomad4 EAS exome

AF:

0.472

Gnomad4 SAS exome

AF:

0.293

Gnomad4 FIN exome

AF:

0.259

Gnomad4 NFE exome

AF:

0.323

Gnomad4 OTH exome

AF:

0.337

GnomAD4 genome

AF:

0.434

AC:

66030

AN:

152060

Hom.:

15103

Cov.:

AF XY:

0.436

AC XY:

32421

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.571

Gnomad4 AMR

AF:

0.391

Gnomad4 ASJ

AF:

0.300

Gnomad4 EAS

AF:

0.558

Gnomad4 SAS

AF:

0.365

Gnomad4 FIN

AF:

0.367

Gnomad4 NFE

AF:

0.376

Gnomad4 OTH

AF:

0.403

Alfa

AF:

0.378

Hom.:

18007

Bravo

AF:

0.436

Asia WGS

AF:

0.489

AC:

1701

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus

Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas.This particular variant (rs2285676) is also associated with increased predisposition to Type II Diabetes Mellitus and its related cardiovascular phenotypes like acute coronary syndrome, stroke. heart failure. -

Diabetes mellitus, transient neonatal, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Hyperinsulinemic hypoglycemia, familial, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Maturity-onset diabetes of the young type 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.3

DANN

Benign

0.20

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