11-17386478-A-G

Variant names:

• chr11-17386478-A-G
• rs2285676
• NM_000525.4:c.*441T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:4
• Conservation: PhyloP100: -0.804

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]

ACMG classification

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.*441T>C		3_prime_UTR_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.*441T>C		3_prime_UTR_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1	c.*441T>C		3_prime_UTR_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1	c.*441T>C		3_prime_UTR_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994	c.*441T>C		3_prime_UTR_variant	Exon 1 of 1		NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65930 AN: 151940 Hom.: 15066 Cov.: 33

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.: 0 AF XY: 0.340 AC XY: 3161 AN XY: 9310

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.: 33 AF XY: 0.436 AC XY: 32421 AN XY: 74330

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:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Type 2 diabetes mellitus Pathogenic:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely risk allele

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.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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperinsulinemic hypoglycemia, familial, 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Other links and lift over

dbSNP: rs2285676; hg19: chr11-17408025;