rs138125678

Positions:

chr11-17387076-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000525.4(KCNJ11):c.1016T>G(p.Val339Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNJ11	NM_000525.4 linkuse as main transcript	c.1016T>G	p.Val339Gly	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2 linkuse as main transcript	c.755T>G	p.Val252Gly	missense_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1 linkuse as main transcript	c.755T>G	p.Val252Gly	missense_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1 linkuse as main transcript	c.755T>G	p.Val252Gly	missense_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5 linkuse as main transcript	c.1016T>G	p.Val339Gly	missense_variant	1/1		NM_000525.4	ENSP00000345708	P1	Q14654-1
KCNJ11	ENST00000528731.1 linkuse as main transcript	c.755T>G	p.Val252Gly	missense_variant	2/2	1		ENSP00000434755		Q14654-2
KCNJ11	ENST00000682350.1 linkuse as main transcript	c.755T>G	p.Val252Gly	missense_variant	2/2			ENSP00000508090		Q14654-2
KCNJ11	ENST00000682764.1 linkuse as main transcript	c.755T>G	p.Val252Gly	missense_variant	2/3			ENSP00000506780		Q14654-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251464

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KCNJ11-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2023

The KCNJ11 c.1016T>G variant is predicted to result in the amino acid substitution p.Val339Gly. This variant was reported in an individual with congenital hyperinsulinism (Supplemental Appendix, Snider et al. 2013. PubMed ID: 23275527). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17408623-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. Though rs138125678 (p.V252G) of KCNJ11 gene was seen in PNDM, its significance remains inconclusive. More studies are required to ascertain the role of rs138125678 variant in MODY. -

Permanent neonatal diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 09, 2017

- -

Type 2 diabetes mellitus;C1833104:Permanent neonatal diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2;C4225365:Maturity-onset diabetes of the young type 13

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;.

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.93

MVP

0.99

MPC

1.8

ClinPred

0.99

GERP RS

5.4

gMVP

0.92

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over