rs386597997

Variant names:

• chr11-17388025-T-A
• rs5219
• NM_000525.4:c.67A>T
• KCNJ11 p.Lys23*

Your query was ambiguous. Multiple possible variants found:

• chr11-17388025-T-A
• chr11-17388025-T-G
• chr11-17388025-T-C

Variant summary

Our verdict is

Pathogenic

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000525.4(KCNJ11):​c.67A>T​(p.Lys23*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 35)
• Consequence: KCNJ11 NM_000525.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 720 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hyperinsulinemic hypoglycemia, familial, 2

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia, G2P, Ambry Genetics, Myriad Women's Health
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• diabetes mellitus, permanent neonatal 2

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• maturity-onset diabetes of the young type 13

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 109 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000525.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	NM_000525.4	MANE Select	c.67A>T	p.Lys23*	stop_gained	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001377296.1		c.-24A>T		5_prime_UTR	Exon 2 of 3	NP_001364225.1	A0A804HHV7
	KCNJ11	NM_001166290.2		c.-16-179A>T		intron	N/A	NP_001159762.1	A0A804HHV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	ENST00000339994.5	TSL:6 MANE Select	c.67A>T	p.Lys23*	stop_gained	Exon 1 of 1	ENSP00000345708.4	Q14654-1
	KCNJ11	ENST00000528731.1	TSL:1	c.-16-179A>T		intron	N/A	ENSP00000434755.1	Q14654-2
	KCNJ11	ENST00000948565.1		c.67A>T	p.Lys23*	stop_gained	Exon 2 of 2	ENSP00000618624.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250574 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.50	N
PhyloP100		2.1
Mutation Taster		=41/159	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5219;

hg19: chr11-17409572;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline