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GeneBe

rs5215

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000525.4(KCNJ11):c.1009G>A(p.Val337Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,613,990 control chromosomes in the GnomAD database, including 342,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 39353 hom., cov: 34)
Exomes 𝑓: 0.64 ( 302925 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.120
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000525.4
BP4
Computational evidence support a benign effect (MetaRNN=8.4797284E-7).
BP6
Variant 11-17387083-C-T is Benign according to our data. Variant chr11-17387083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17387083-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNJ11NM_000525.4 linkuse as main transcriptc.1009G>A p.Val337Ile missense_variant 1/1 ENST00000339994.5
KCNJ11NM_001166290.2 linkuse as main transcriptc.748G>A p.Val250Ile missense_variant 2/2
KCNJ11NM_001377296.1 linkuse as main transcriptc.748G>A p.Val250Ile missense_variant 3/3
KCNJ11NM_001377297.1 linkuse as main transcriptc.748G>A p.Val250Ile missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNJ11ENST00000339994.5 linkuse as main transcriptc.1009G>A p.Val337Ile missense_variant 1/1 NM_000525.4 P1Q14654-1
KCNJ11ENST00000528731.1 linkuse as main transcriptc.748G>A p.Val250Ile missense_variant 2/21 Q14654-2
KCNJ11ENST00000682350.1 linkuse as main transcriptc.748G>A p.Val250Ile missense_variant 2/2 Q14654-2
KCNJ11ENST00000682764.1 linkuse as main transcriptc.748G>A p.Val250Ile missense_variant 2/3 Q14654-2

Frequencies

GnomAD3 genomes
AF:
0.708
AC:
107545
AN:
152006
Hom.:
39303
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.911
Gnomad AMI
AF:
0.482
Gnomad AMR
AF:
0.670
Gnomad ASJ
AF:
0.645
Gnomad EAS
AF:
0.646
Gnomad SAS
AF:
0.625
Gnomad FIN
AF:
0.531
Gnomad MID
AF:
0.697
Gnomad NFE
AF:
0.637
Gnomad OTH
AF:
0.687
GnomAD3 exomes
AF:
0.638
AC:
160506
AN:
251456
Hom.:
52127
AF XY:
0.634
AC XY:
86160
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.916
Gnomad AMR exome
AF:
0.618
Gnomad ASJ exome
AF:
0.637
Gnomad EAS exome
AF:
0.635
Gnomad SAS exome
AF:
0.629
Gnomad FIN exome
AF:
0.522
Gnomad NFE exome
AF:
0.630
Gnomad OTH exome
AF:
0.635
GnomAD4 exome
AF:
0.641
AC:
937700
AN:
1461864
Hom.:
302925
Cov.:
73
AF XY:
0.639
AC XY:
464957
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.924
Gnomad4 AMR exome
AF:
0.623
Gnomad4 ASJ exome
AF:
0.641
Gnomad4 EAS exome
AF:
0.633
Gnomad4 SAS exome
AF:
0.630
Gnomad4 FIN exome
AF:
0.523
Gnomad4 NFE exome
AF:
0.639
Gnomad4 OTH exome
AF:
0.654
GnomAD4 genome
AF:
0.708
AC:
107657
AN:
152126
Hom.:
39353
Cov.:
34
AF XY:
0.702
AC XY:
52184
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.911
Gnomad4 AMR
AF:
0.670
Gnomad4 ASJ
AF:
0.645
Gnomad4 EAS
AF:
0.647
Gnomad4 SAS
AF:
0.625
Gnomad4 FIN
AF:
0.531
Gnomad4 NFE
AF:
0.637
Gnomad4 OTH
AF:
0.686
Alfa
AF:
0.650
Hom.:
69523
Bravo
AF:
0.722
TwinsUK
AF:
0.650
AC:
2410
ALSPAC
AF:
0.637
AC:
2456
ESP6500AA
AF:
0.913
AC:
4018
ESP6500EA
AF:
0.639
AC:
5488
ExAC
AF:
0.645
AC:
78262
Asia WGS
AF:
0.663
AC:
2305
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 02, 2021- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Diabetes mellitus, transient neonatal, 3 Benign:2
Benign, criteria provided, single submitterclinical testingPars Genome LabJul 01, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxSep 10, 2018This variant is associated with the following publications: (PMID: 31118516, 30389748, 26551672, 27398621, 17257281, 22958899) -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Hyperinsulinemic hypoglycemia, familial, 2 Benign:2
Benign, criteria provided, single submitterclinical testingPars Genome LabJul 01, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Diabetes mellitus, permanent neonatal 2 Benign:1
Benign, criteria provided, single submitterclinical testingPars Genome LabJul 01, 2021- -
Permanent neonatal diabetes mellitus Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Maturity-onset diabetes of the young type 13 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Type 2 diabetes mellitus Other:1
association, no assertion criteria providedresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Mutations can cause decreased production of insulin and secretion. This can lead to MODY which is responsive to oral sulfonylureas. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.41
Cadd
Benign
8.3
Dann
Benign
0.93
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.070
N
LIST_S2
Benign
0.48
T;.
MetaRNN
Benign
8.5e-7
T;T
MetaSVM
Benign
-0.82
T
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.10
N;N
REVEL
Benign
0.27
Sift
Benign
0.15
T;T
Sift4G
Benign
0.20
T;T
Vest4
0.017
MPC
0.51
ClinPred
0.0052
T
GERP RS
-6.0
gMVP
0.22

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.

Other links and lift over

dbSNP: rs5215; hg19: chr11-17408630; COSMIC: COSV60595714; COSMIC: COSV60595714; API