11-17382092-T-C

Variant names:

• chr11-17382092-T-C
• rs1557765
• ENST00000568280.1:n.1444T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000568280.1(ENSG00000260196):​n.1444T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 152,212 control chromosomes in the GnomAD database, including 38,474 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.70 (38459 hom., cov: 33)
  • Exomes 𝑓: 0.65 (15 hom.)
• Consequence: ENSG00000260196 ENST00000568280.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 44 publications found

Genes affected

ENSG00000260196 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000260196	ENST00000568280.1	n.1444T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
KCNJ11	ENST00000682764.1	c.*50+4777A>G		intron_variant	Intron 2 of 2			ENSP00000506780.1

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106151 AN: 152028 Hom.: 38411 Cov.: 33

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.684

GnomAD4 exome AF: 0.652 AC: 43 AN: 66 Hom.: 15 Cov.: 0 AF XY: 0.620 AC XY: 31 AN XY: 50

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.679 AC: 38 AN: 56

Other (OTH) AF: 0.333 AC: 2 AN: 6

GnomAD4 genome AF: 0.698 AC: 106260 AN: 152146 Hom.: 38459 Cov.: 33 AF XY: 0.693 AC XY: 51562 AN XY: 74384

African (AFR) AF: 0.907 AC: 37658 AN: 41534

American (AMR) AF: 0.666 AC: 10177 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2224 AN: 3470

East Asian (EAS) AF: 0.647 AC: 3348 AN: 5172

South Asian (SAS) AF: 0.625 AC: 3019 AN: 4830

European-Finnish (FIN) AF: 0.519 AC: 5486 AN: 10566

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42235 AN: 67970

Other (OTH) AF: 0.683 AC: 1441 AN: 2110

Alfa AF: 0.642 Hom.: 26404

Bravo AF: 0.714

Asia WGS AF: 0.665 AC: 2314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.59
DANN	Benign	0.56
PhyloP100		-1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1557765; hg19: chr11-17403639;