rs750689750

Positions:

chr11-17386998-C-T

Variant summary

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

The NM_000525.4(KCNJ11):c.1094G>A(p.Arg365His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R365R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.404

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNJ11	NM_000525.4 linkuse as main transcript	c.1094G>A	p.Arg365His	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2 linkuse as main transcript	c.833G>A	p.Arg278His	missense_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1 linkuse as main transcript	c.833G>A	p.Arg278His	missense_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1 linkuse as main transcript	c.833G>A	p.Arg278His	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.1094G>A	p.Arg365His	missense_variant	1/1		NM_000525.4	ENSP00000345708	P1	Q14654-1
KCNJ11	ENST00000528731.1 linkuse as main transcript	c.833G>A	p.Arg278His	missense_variant	2/2	1		ENSP00000434755		Q14654-2
KCNJ11	ENST00000682350.1 linkuse as main transcript	c.833G>A	p.Arg278His	missense_variant	2/2			ENSP00000508090		Q14654-2
KCNJ11	ENST00000682764.1 linkuse as main transcript	c.833G>A	p.Arg278His	missense_variant	2/3			ENSP00000506780		Q14654-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250856

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461452

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726974

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:

0.0000464

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 generally cause decreased production and secretion of insulin. This can lead to MODY. However, this particular variant (rs750689750) prevalence is too low in MODY cases and it is not associated with the condition. More evidence required to ascertain its significance. -

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

Aug 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

-0.016

Eigen_PC

Benign

0.027

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

T;.

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.59

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.75

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.033

D;D

Sift4G

Benign

0.14

T;T

Vest4

0.65

MutPred

0.78

Loss of loop (P = 0.0112);.;

MVP

0.83

MPC

1.4

ClinPred

0.13

GERP RS

4.4

gMVP

0.40

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