NM_000525.4:c.-54C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000525.4(KCNJ11):c.-54C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,539,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.54

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4 link	c.-54C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_000525.4 link	c.-54C>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5 link	c.-54C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000339994.5 link	c.-54C>T		5_prime_UTR_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1387138

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

690262

show subpopulations

African (AFR)

AF:

0.0000625

AC:

AN:

32016

American (AMR)

AF:

0.00

AC:

AN:

43890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25230

East Asian (EAS)

AF:

0.00

AC:

AN:

38942

South Asian (SAS)

AF:

0.00

AC:

AN:

84040

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

48574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.00000856

AC:

AN:

1051138

Other (OTH)

AF:

0.00

AC:

AN:

57720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000526

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2;C4225365:Maturity-onset diabetes of the young type 13;C5394296:Diabetes mellitus, permanent neonatal 2

Uncertain:1

Mar 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. It is also associated with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of this particular variant (rs1016780684) in MODY yet. -

Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2;C5393570:Permanent neonatal diabetes mellitus 1

Uncertain:1

Nov 14, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

5.3

(source)

DANN

Benign

0.73

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over