11-17387430-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000525.4(KCNJ11):c.662G>A(p.Arg221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000525.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.662G>A | p.Arg221His | missense_variant | Exon 1 of 1 | ENST00000339994.5 | NP_000516.3 | |
KCNJ11 | NM_001166290.2 | c.401G>A | p.Arg134His | missense_variant | Exon 2 of 2 | NP_001159762.1 | ||
KCNJ11 | NM_001377296.1 | c.401G>A | p.Arg134His | missense_variant | Exon 3 of 3 | NP_001364225.1 | ||
KCNJ11 | NM_001377297.1 | c.401G>A | p.Arg134His | missense_variant | Exon 2 of 2 | NP_001364226.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250370Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135426
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461292Hom.: 0 Cov.: 68 AF XY: 0.00000825 AC XY: 6AN XY: 726950
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.662G>A (p.R221H) alteration is located in exon 1 (coding exon 1) of the KCNJ11 gene. This alteration results from a G to A substitution at nucleotide position 662, causing the arginine (R) at amino acid position 221 to be replaced by a histidine (H). The in silico prediction for the p.R221H alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hyperinsulinemia Uncertain:1
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. This particular variant rs768909861 has been studied in Hyperinsulinemic Hypoglycemia cases, but significant association with the phenotype is not seen. More studies are required to ascertain the role of this variant in MODY. -
Type 2 diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2;C4225365:Maturity-onset diabetes of the young type 13;C5394296:Diabetes mellitus, permanent neonatal 2 Uncertain:1
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not provided Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 556784). This missense change has been observed in individual(s) with hyperinsulinism and/or type 2 diabetes mellitus (PMID: 27173951, 33046911). This variant is present in population databases (rs768909861, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 221 of the KCNJ11 protein (p.Arg221His). -
Permanent neonatal diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at