Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000525.4(KCNJ11):c.570C>T(p.Ala190Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,611,284 control chromosomes in the GnomAD database, including 72,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A190A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 5170 hom., cov: 33)

Exomes 𝑓: 0.29 ( 66904 hom. )

Consequence

KCNJ11
NM_000525.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.279

Publications

55 publications found

Variant links:

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

KCNJ11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 11-17387522-G-A is Benign according to our data. Variant chr11-17387522-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.279 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.479 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNJ11	NM_000525.4	MANE Select	c.570C>T	p.Ala190Ala	synonymous	Exon 1 of 1	NP_000516.3
KCNJ11	NM_001166290.2		c.309C>T	p.Ala103Ala	synonymous	Exon 2 of 2	NP_001159762.1
KCNJ11	NM_001377296.1		c.309C>T	p.Ala103Ala	synonymous	Exon 3 of 3	NP_001364225.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNJ11	ENST00000339994.5	TSL:6 MANE Select	c.570C>T	p.Ala190Ala	synonymous	Exon 1 of 1	ENSP00000345708.4
KCNJ11	ENST00000528731.1	TSL:1	c.309C>T	p.Ala103Ala	synonymous	Exon 2 of 2	ENSP00000434755.1
KCNJ11	ENST00000682350.1		c.309C>T	p.Ala103Ala	synonymous	Exon 2 of 2	ENSP00000508090.1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

35011

AN:

152016

Hom.:

5169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0667

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.494

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.257

AC:

63365

AN:

246490

AF XY:

0.257

show subpopulations

Gnomad AFR exome

AF:

0.0605

Gnomad AMR exome

AF:

0.142

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.490

Gnomad FIN exome

AF:

0.336

Gnomad NFE exome

AF:

0.299

Gnomad OTH exome

AF:

0.255

GnomAD4 exome

AF:

0.294

AC:

429328

AN:

1459150

Hom.:

66904

Cov.:

AF XY:

0.290

AC XY:

210455

AN XY:

725796

show subpopulations

African (AFR)

AF:

0.0562

AC:

1880

AN:

33476

American (AMR)

AF:

0.146

AC:

6512

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5050

AN:

26124

East Asian (EAS)

AF:

0.474

AC:

18789

AN:

39676

South Asian (SAS)

AF:

0.165

AC:

14225

AN:

86202

European-Finnish (FIN)

AF:

0.335

AC:

17230

AN:

51498

Middle Eastern (MID)

AF:

0.180

AC:

1036

AN:

5768

European-Non Finnish (NFE)

AF:

0.313

AC:

347886

AN:

1111462

Other (OTH)

AF:

0.277

AC:

16720

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

20839

41678

62517

83356

104195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11220

22440

33660

44880

56100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.230

AC:

35014

AN:

152134

Hom.:

5170

Cov.:

AF XY:

0.233

AC XY:

17302

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0666

AC:

2765

AN:

41546

American (AMR)

AF:

0.185

AC:

2822

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

683

AN:

3468

East Asian (EAS)

AF:

0.495

AC:

2549

AN:

5146

South Asian (SAS)

AF:

0.167

AC:

807

AN:

4822

European-Finnish (FIN)

AF:

0.349

AC:

3693

AN:

10582

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.308

AC:

20919

AN:

67962

Other (OTH)

AF:

0.216

AC:

456

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1291

2582

3873

5164

6455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.256

Hom.:

6666

Bravo

AF:

0.210

Asia WGS

AF:

0.292

AC:

1011

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hyperinsulinemic hypoglycemia, familial, 2 (2)

not specified (2)

Diabetes mellitus, transient neonatal, 3 (1)

Maturity-onset diabetes of the young type 13 (1)

Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.5

(source)

DANN

Benign

0.90

PhyloP100

0.28

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs5218

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over