rs2285676

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000525.4(KCNJ11):c.*441T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 170,132 control chromosomes in the GnomAD database, including 16,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.43 ( 15103 hom., cov: 33)

Exomes 𝑓: 0.34 ( 1139 hom. )

Consequence

KCNJ11
NM_000525.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:4

Conservation

PhyloP100: -0.804

Publications

44 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hyperinsulinemic hypoglycemia, familial, 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 11-17386478-A-G is Benign according to our data. Variant chr11-17386478-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 303722.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 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	Effect	Exon Rank	Protein	UniProt
KCNJ11	NM_000525.4	MANE Select	c.*441T>C	3_prime_UTR	Exon 1 of 1	NP_000516.3
KCNJ11	NM_001166290.2		c.*441T>C	3_prime_UTR	Exon 2 of 2	NP_001159762.1	A0A804HHV7
KCNJ11	NM_001377296.1		c.*441T>C	3_prime_UTR	Exon 3 of 3	NP_001364225.1	A0A804HHV7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNJ11	ENST00000339994.5	TSL:6 MANE Select	c.*441T>C	3_prime_UTR	Exon 1 of 1	ENSP00000345708.4	Q14654-1
KCNJ11	ENST00000528731.1	TSL:1	c.*441T>C	3_prime_UTR	Exon 2 of 2	ENSP00000434755.1	Q14654-2
KCNJ11	ENST00000948565.1		c.*441T>C	3_prime_UTR	Exon 2 of 2	ENSP00000618624.1

Frequencies

GnomAD3 genomes

AF:

0.434

AC:

65930

AN:

151940

Hom.:

15066

Cov.:

show subpopulations

Gnomad AFR

AF:

0.570

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.391

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.399

GnomAD4 exome

AF:

0.337

AC:

6085

AN:

18072

Hom.:

1139

Cov.:

AF XY:

0.340

AC XY:

3161

AN XY:

9310

show subpopulations

African (AFR)

AF:

0.506

AC:

235

AN:

464

American (AMR)

AF:

0.333

AC:

906

AN:

2724

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

AN:

332

East Asian (EAS)

AF:

0.472

AC:

681

AN:

1444

South Asian (SAS)

AF:

0.293

AC:

431

AN:

1472

European-Finnish (FIN)

AF:

0.259

AC:

106

AN:

410

Middle Eastern (MID)

AF:

0.367

AC:

AN:

European-Non Finnish (NFE)

AF:

0.323

AC:

3316

AN:

10276

Other (OTH)

AF:

0.337

AC:

300

AN:

890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

189

377

566

754

943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.434

AC:

66030

AN:

152060

Hom.:

15103

Cov.:

AF XY:

0.436

AC XY:

32421

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.571

AC:

23675

AN:

41496

American (AMR)

AF:

0.391

AC:

5984

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1041

AN:

3470

East Asian (EAS)

AF:

0.558

AC:

2871

AN:

5142

South Asian (SAS)

AF:

0.365

AC:

1762

AN:

4822

European-Finnish (FIN)

AF:

0.367

AC:

3882

AN:

10590

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.376

AC:

25568

AN:

67938

Other (OTH)

AF:

0.403

AC:

850

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1923

3847

5770

7694

9617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.391

Hom.:

33237

Bravo

AF:

0.436

Asia WGS

AF:

0.489

AC:

1701

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Diabetes mellitus, transient neonatal, 3 (1)

Hyperinsulinemic hypoglycemia, familial, 2 (1)

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

not provided (1)

Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.3

(source)

DANN

Benign

0.20

PhyloP100

-0.80

Mutation Taster

=100/0

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.

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

Computational scores

Splicing

Publications

Other links and lift over