rs1554901596
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_000525.4(KCNJ11):c.967_968insG(p.Asp323GlyfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D323D) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
KCNJ11
NM_000525.4 frameshift
NM_000525.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
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 Likely_pathogenic. Variant got 7 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-17387124-T-TC is Pathogenic according to our data. Variant chr11-17387124-T-TC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478917.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.967_968insG | p.Asp323GlyfsTer28 | frameshift_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.706_707insG | p.Asp236GlyfsTer28 | frameshift_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.706_707insG | p.Asp236GlyfsTer28 | frameshift_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.706_707insG | p.Asp236GlyfsTer28 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.967_968insG | p.Asp323GlyfsTer28 | frameshift_variant | 1/1 | NM_000525.4 | P1 | ||
KCNJ11 | ENST00000528731.1 | c.706_707insG | p.Asp236GlyfsTer28 | frameshift_variant | 2/2 | 1 | |||
KCNJ11 | ENST00000682350.1 | c.706_707insG | p.Asp236GlyfsTer28 | frameshift_variant | 2/2 | ||||
KCNJ11 | ENST00000682764.1 | c.706_707insG | p.Asp236GlyfsTer28 | frameshift_variant | 2/3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 67
GnomAD4 exome
Cov.:
67
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Type 2 diabetes mellitus;C4225365:Maturity-onset diabetes of the young type 13 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital | Aug 31, 2017 | - - |
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 cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. It is also associated with with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of rs1554901596 variant in MODY yet. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at