rs8175351
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000525.4(KCNJ11):c.1143G>A(p.Lys381=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,174 control chromosomes in the GnomAD database, including 358 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 0.013 ( 21 hom., cov: 34)
Exomes 𝑓: 0.019 ( 337 hom. )
Consequence
KCNJ11
NM_000525.4 synonymous
NM_000525.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.818
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 -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
Variant 11-17386949-C-T is Benign according to our data. Variant chr11-17386949-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158672.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Uncertain_significance=2}. Variant chr11-17386949-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.818 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1937/152300) while in subpopulation NFE AF= 0.021 (1429/68004). AF 95% confidence interval is 0.0201. There are 21 homozygotes in gnomad4. There are 853 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 21 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.1143G>A | p.Lys381= | synonymous_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.882G>A | p.Lys294= | synonymous_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.882G>A | p.Lys294= | synonymous_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.882G>A | p.Lys294= | synonymous_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.1143G>A | p.Lys381= | synonymous_variant | 1/1 | NM_000525.4 | P1 | ||
KCNJ11 | ENST00000528731.1 | c.882G>A | p.Lys294= | synonymous_variant | 2/2 | 1 | |||
KCNJ11 | ENST00000682350.1 | c.882G>A | p.Lys294= | synonymous_variant | 2/2 | ||||
KCNJ11 | ENST00000682764.1 | c.882G>A | p.Lys294= | synonymous_variant | 2/3 |
Frequencies
GnomAD3 genomes ? AF: 0.0127 AC: 1938AN: 152182Hom.: 21 Cov.: 34
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GnomAD3 exomes AF: 0.0126 AC: 3147AN: 250258Hom.: 39 AF XY: 0.0126 AC XY: 1703AN XY: 135312
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GnomAD4 exome AF: 0.0186 AC: 27239AN: 1460874Hom.: 337 Cov.: 32 AF XY: 0.0183 AC XY: 13305AN XY: 726644
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GnomAD4 genome ? AF: 0.0127 AC: 1937AN: 152300Hom.: 21 Cov.: 34 AF XY: 0.0115 AC XY: 853AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 19, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 24, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2021 | This variant is associated with the following publications: (PMID: 16429405, 17316607, 15504982) - |
Hyperinsulinemia 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. However, significance of rs8175351 is uncertain in Hyperinsulinemic Hypoglycemia of Infancy. - |
Diabetes mellitus, transient neonatal, 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Permanent neonatal diabetes mellitus Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Maturity-onset diabetes of the young type 13 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
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