rs386597997

Variant names:

• chr11-17388025-T-C
• rs5219
• NM_000525.4:c.67A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000525.4(KCNJ11):​c.67A>G​(p.Lys23Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,613,446 control chromosomes in the GnomAD database, including 344,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.71 (40302 hom., cov: 35)
  • Exomes 𝑓: 0.64 (303818 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 2.12
• Publications: 713 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8824744E-7).
• BP6: Variant 11-17388025-T-C is Benign according to our data. Variant chr11-17388025-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	NM_000525.4	MANE Select	c.67A>G	p.Lys23Glu	missense	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001377296.1		c.-24A>G		5_prime_UTR	Exon 2 of 3	NP_001364225.1
	KCNJ11	NM_001166290.2		c.-16-179A>G		intron	N/A	NP_001159762.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	ENST00000339994.5	TSL:6 MANE Select	c.67A>G	p.Lys23Glu	missense	Exon 1 of 1	ENSP00000345708.4
	KCNJ11	ENST00000528731.1	TSL:1	c.-16-179A>G		intron	N/A	ENSP00000434755.1
	KCNJ11	ENST00000948565.1		c.67A>G	p.Lys23Glu	missense	Exon 2 of 2	ENSP00000618624.1

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108604 AN: 152122 Hom.: 40242 Cov.: 35

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.692

GnomAD2 exomes AF: 0.640 AC: 160417 AN: 250574 AF XY: 0.635

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.523

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.642 AC: 938548 AN: 1461206 Hom.: 303818 Cov.: 64 AF XY: 0.640 AC XY: 465281 AN XY: 726874

African (AFR) AF: 0.946 AC: 31681 AN: 33480

American (AMR) AF: 0.625 AC: 27924 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16748 AN: 26134

East Asian (EAS) AF: 0.634 AC: 25146 AN: 39692

South Asian (SAS) AF: 0.631 AC: 54393 AN: 86252

European-Finnish (FIN) AF: 0.524 AC: 27779 AN: 52992

Middle Eastern (MID) AF: 0.725 AC: 4180 AN: 5768

European-Non Finnish (NFE) AF: 0.640 AC: 711099 AN: 1111794

Other (OTH) AF: 0.656 AC: 39598 AN: 60384

GnomAD4 genome AF: 0.714 AC: 108727 AN: 152240 Hom.: 40302 Cov.: 35 AF XY: 0.708 AC XY: 52690 AN XY: 74440

African (AFR) AF: 0.933 AC: 38784 AN: 41556

American (AMR) AF: 0.672 AC: 10285 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2239 AN: 3468

East Asian (EAS) AF: 0.646 AC: 3332 AN: 5158

South Asian (SAS) AF: 0.626 AC: 3025 AN: 4830

European-Finnish (FIN) AF: 0.532 AC: 5639 AN: 10602

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.637 AC: 43315 AN: 68000

Other (OTH) AF: 0.690 AC: 1461 AN: 2116

Alfa AF: 0.659 Hom.: 147614

Bravo AF: 0.730

TwinsUK AF: 0.650 AC: 2409

ALSPAC AF: 0.638 AC: 2457

ESP6500AA AF: 0.931 AC: 4095

ESP6500EA AF: 0.639 AC: 5490

ExAC AF: 0.647 AC: 78506

Asia WGS AF: 0.667 AC: 2321 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hyperinsulinemic hypoglycemia, familial, 2 (2)
-	-	2	not specified (2)
-	-	2	Permanent neonatal diabetes mellitus (3)
-	-	1	Diabetes mellitus type 2, susceptibility to (1)
-	-	1	Diabetes mellitus, transient neonatal, 3 (1)
-	-	1	Hyperinsulinism, Dominant/Recessive (1)
-	-	1	KCNJ11-related disorder (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 13 (1)
-	-	1	Transient Neonatal Diabetes, Dominant (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.92
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.086	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.17
Sift	Benign	0.32	T
Sift4G	Benign	0.23	T
Vest4		0.0090
MPC		0.86
ClinPred		0.0012	T
GERP RS		4.3
gMVP		0.51
Mutation Taster		=95/5	polymorphism (auto)

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: rs5219; hg19: chr11-17409572; COSMIC: COSV56858357; COSMIC: COSV56858357;