rs104894248
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000525.4(KCNJ11):c.776A>G(p.His259Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
KCNJ11
NM_000525.4 missense
NM_000525.4 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 8.02
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.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000525.4
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 11-17387316-T-C is Pathogenic according to our data. Variant chr11-17387316-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8677.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.776A>G | p.His259Arg | missense_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.515A>G | p.His172Arg | missense_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.515A>G | p.His172Arg | missense_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.515A>G | p.His172Arg | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.776A>G | p.His259Arg | missense_variant | 1/1 | NM_000525.4 | P1 | ||
KCNJ11 | ENST00000528731.1 | c.515A>G | p.His172Arg | missense_variant | 2/2 | 1 | |||
KCNJ11 | ENST00000682350.1 | c.515A>G | p.His172Arg | missense_variant | 2/2 | ||||
KCNJ11 | ENST00000682764.1 | c.515A>G | p.His172Arg | missense_variant | 2/3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151798Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251358Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135856
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461890Hom.: 0 Cov.: 67 AF XY: 0.00000825 AC XY: 6AN XY: 727248
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Type 2 diabetes mellitus Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 29, 2023 | - - |
Hyperinsulinemic hypoglycemia, familial, 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 17, 2020 | The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
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 Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of rs104894248 variant in MODY yet. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Vest4
MutPred
Gain of catalytic residue at H259 (P = 0.066);.;
MVP
MPC
ClinPred
D
GERP RS
gMVP
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