rs1371185696

Positions:

chr11-17387532-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000525.4(KCNJ11):c.560C>T(p.Ala187Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-17387532-G-A is Pathogenic according to our data. Variant chr11-17387532-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4 linkuse as main transcript	c.560C>T	p.Ala187Val	missense_variant	1/1	ENST00000339994.5	NP_000516.3	Q14654-1B2RC52
KCNJ11	NM_001166290.2 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	2/2		NP_001159762.1	Q14654-2A0A804HHV7
KCNJ11	NM_001377296.1 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1 linkuse as main transcript	c.299C>T	p.Ala100Val	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.560C>T	p.Ala187Val	missense_variant	1/1	6	NM_000525.4	ENSP00000345708.4		Q14654-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

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

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459914

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726216

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

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:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 187 of the KCNJ11 protein (p.Ala187Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive congenital hyperinsulinism and/or focal congenital hyperinsulinism (PMID: 11395395, 21422196, 21812132). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ11 protein function. This variant disrupts the p.Ala187 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ11-related conditions (PMID: 21422196, 23652837), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 21, 2017

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, flagged submission

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. It is also associated with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of this particular variant (rs1371185696) in MODY yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;.

Vest4

0.94

MutPred

0.96

Loss of catalytic residue at A187 (P = 0.049);.;.;

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.2

gMVP

1.0

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