rs116392938
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1
The NM_000525.4(KCNJ11):c.843C>T(p.Leu281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,614,186 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 1 hom. )
Consequence
KCNJ11
NM_000525.4 synonymous
NM_000525.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.75
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
?
Variant 11-17387249-G-A is Benign according to our data. Variant chr11-17387249-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211227.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=5, Uncertain_significance=2}. Variant chr11-17387249-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-2.75 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000427 (65/152326) while in subpopulation EAS AF= 0.00579 (30/5180). AF 95% confidence interval is 0.00417. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.843C>T | p.Leu281= | synonymous_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.582C>T | p.Leu194= | synonymous_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.582C>T | p.Leu194= | synonymous_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.582C>T | p.Leu194= | synonymous_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.843C>T | p.Leu281= | synonymous_variant | 1/1 | NM_000525.4 | P1 | ||
KCNJ11 | ENST00000528731.1 | c.582C>T | p.Leu194= | synonymous_variant | 2/2 | 1 | |||
KCNJ11 | ENST00000682350.1 | c.582C>T | p.Leu194= | synonymous_variant | 2/2 | ||||
KCNJ11 | ENST00000682764.1 | c.582C>T | p.Leu194= | synonymous_variant | 2/3 |
Frequencies
GnomAD3 genomes ? AF: 0.000434 AC: 66AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000402 AC: 101AN: 251388Hom.: 1 AF XY: 0.000375 AC XY: 51AN XY: 135876
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GnomAD4 exome AF: 0.000199 AC: 291AN: 1461860Hom.: 1 Cov.: 68 AF XY: 0.000194 AC XY: 141AN XY: 727232
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GnomAD4 genome ? AF: 0.000427 AC: 65AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39AN XY: 74474
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:6
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | KCNJ11: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 14, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2020 | This variant is associated with the following publications: (PMID: 26740944) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 23, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 30, 2020 | - - |
Hyperinsulinemia 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, the role of this particular variant (rs116392938) of KCNJ11 gene in congenital hyperinsulinism and MODY remains uncertain. - |
Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Diabetes mellitus, transient neonatal, 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Permanent neonatal diabetes mellitus Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 22, 2019 | - - |
Maturity-onset diabetes of the young type 13 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at