chr11-17387083-C-T

Variant names:

• chr11-17387083-C-T
• rs5215
• NM_000525.4:c.1009G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000525.4(KCNJ11):​c.1009G>A​(p.Val337Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,613,990 control chromosomes in the GnomAD database, including 342,278 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 (39353 hom., cov: 34)
  • Exomes 𝑓: 0.64 (302925 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -0.120
• Publications: 391 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_000525.4
• BP4: Computational evidence support a benign effect (MetaRNN=8.4797284E-7).
• BP6: Variant 11-17387083-C-T is Benign according to our data. Variant chr11-17387083-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 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.1009G>A	p.Val337Ile	missense	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001166290.2		c.748G>A	p.Val250Ile	missense	Exon 2 of 2	NP_001159762.1
	KCNJ11	NM_001377296.1		c.748G>A	p.Val250Ile	missense	Exon 3 of 3	NP_001364225.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	ENST00000339994.5	TSL:6 MANE Select	c.1009G>A	p.Val337Ile	missense	Exon 1 of 1	ENSP00000345708.4
	KCNJ11	ENST00000528731.1	TSL:1	c.748G>A	p.Val250Ile	missense	Exon 2 of 2	ENSP00000434755.1
	KCNJ11	ENST00000948565.1		c.1009G>A	p.Val337Ile	missense	Exon 2 of 2	ENSP00000618624.1

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107545 AN: 152006 Hom.: 39303 Cov.: 34

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.687

GnomAD2 exomes AF: 0.638 AC: 160506 AN: 251456 AF XY: 0.634

Gnomad AFR exome AF: 0.916

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.641 AC: 937700 AN: 1461864 Hom.: 302925 Cov.: 73 AF XY: 0.639 AC XY: 464957 AN XY: 727236

African (AFR) AF: 0.924 AC: 30931 AN: 33480

American (AMR) AF: 0.623 AC: 27860 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16749 AN: 26136

East Asian (EAS) AF: 0.633 AC: 25142 AN: 39700

South Asian (SAS) AF: 0.630 AC: 54339 AN: 86258

European-Finnish (FIN) AF: 0.523 AC: 27945 AN: 53416

Middle Eastern (MID) AF: 0.724 AC: 4174 AN: 5766

European-Non Finnish (NFE) AF: 0.639 AC: 711073 AN: 1111988

Other (OTH) AF: 0.654 AC: 39487 AN: 60396

GnomAD4 genome AF: 0.708 AC: 107657 AN: 152126 Hom.: 39353 Cov.: 34 AF XY: 0.702 AC XY: 52184 AN XY: 74352

African (AFR) AF: 0.911 AC: 37832 AN: 41540

American (AMR) AF: 0.670 AC: 10243 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2240 AN: 3472

East Asian (EAS) AF: 0.647 AC: 3333 AN: 5148

South Asian (SAS) AF: 0.625 AC: 3010 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5619 AN: 10586

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43283 AN: 67962

Other (OTH) AF: 0.686 AC: 1451 AN: 2114

Alfa AF: 0.656 Hom.: 149415

Bravo AF: 0.722

TwinsUK AF: 0.650 AC: 2410

ALSPAC AF: 0.637 AC: 2456

ESP6500AA AF: 0.913 AC: 4018

ESP6500EA AF: 0.639 AC: 5488

ExAC AF: 0.645 AC: 78262

Asia WGS AF: 0.663 AC: 2305 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Diabetes mellitus, transient neonatal, 3 (2)
-	-	2	Hyperinsulinemic hypoglycemia, familial, 2 (2)
-	-	1	Diabetes mellitus, permanent neonatal 2 (1)
-	-	1	Maturity-onset diabetes of the young type 13 (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.3
DANN	Benign	0.93
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-0.82	T
PhyloP100		-0.12
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.27
Sift	Benign	0.15	T
Sift4G	Benign	0.20	T
Vest4		0.017
MPC		0.51
ClinPred		0.0052	T
GERP RS		-6.0
gMVP		0.22
Mutation Taster		=97/3	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: rs5215; hg19: chr11-17408630; COSMIC: COSV60595714; COSMIC: COSV60595714;