NM_000525.4:c.1040G>A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000525.4(KCNJ11):c.1040G>A(p.Arg347His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000525.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.1040G>A | p.Arg347His | missense_variant | Exon 1 of 1 | ENST00000339994.5 | NP_000516.3 | |
KCNJ11 | NM_001166290.2 | c.779G>A | p.Arg260His | missense_variant | Exon 2 of 2 | NP_001159762.1 | ||
KCNJ11 | NM_001377296.1 | c.779G>A | p.Arg260His | missense_variant | Exon 3 of 3 | NP_001364225.1 | ||
KCNJ11 | NM_001377297.1 | c.779G>A | p.Arg260His | missense_variant | Exon 2 of 2 | NP_001364226.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.1040G>A | p.Arg347His | missense_variant | Exon 1 of 1 | 6 | NM_000525.4 | ENSP00000345708.4 | ||
KCNJ11 | ENST00000528731.1 | c.779G>A | p.Arg260His | missense_variant | Exon 2 of 2 | 1 | ENSP00000434755.1 | |||
KCNJ11 | ENST00000682350.1 | c.779G>A | p.Arg260His | missense_variant | Exon 2 of 2 | ENSP00000508090.1 | ||||
KCNJ11 | ENST00000682764.1 | c.779G>A | p.Arg260His | missense_variant | Exon 2 of 3 | ENSP00000506780.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251414Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727240
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: KCNJ11 c.1040G>A (p.Arg347His) results in a non-conservative amino acid change located in the inward rectifier potassium channel, C-terminal domain (IPR041647) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251414 control chromosomes, found exclusively within the Non-Finnish European subpopulation at a frequency of 5.3e-05 in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1040G>A has been reported in the literature as a VUS in settings of multigene testing in an individual affected with congenital hyperinsulinism and in an individual suspected of monogenic diabetes with a positive family history (Kapoor_2013, Donath_2019). These reports do not provide unequivocal conclusions about association of the variant with congenital hyperinsulinism or monogenic diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The c.1040G>A (p.R347H) 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 1040, causing the arginine (R) at amino acid position 347 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (6/251414) total alleles studied. The highest observed frequency was 0.01% (6/113716) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
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
- -
Maturity onset diabetes mellitus in young 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. However, no sufficient evidence is found to ascertain the role of this particular variant (rs771797701) in MODY yet. -
Monogenic diabetes Uncertain:1
ACMG criteria: PP3 (9 predictors)=VUS -
not provided Uncertain:1
- -
Permanent neonatal diabetes mellitus Uncertain:1
- -
Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1
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. -
Permanent neonatal diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1
- -
Maturity-onset diabetes of the young type 13 Uncertain:1
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at