rs28936678
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000525.4(KCNJ11):āc.440T>Cā(p.Leu147Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,726 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: not found (cov: 33)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
KCNJ11
NM_000525.4 missense
NM_000525.4 missense
Scores
4
9
4
Clinical Significance
Conservation
PhyloP100: 3.94
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 helix (size 28) in uniprot entity KCJ11_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_000525.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
Variant 11-17387652-A-G is Pathogenic according to our data. Variant chr11-17387652-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8665.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.440T>C | p.Leu147Pro | missense_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.179T>C | p.Leu60Pro | missense_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.179T>C | p.Leu60Pro | missense_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.179T>C | p.Leu60Pro | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.440T>C | p.Leu147Pro | missense_variant | 1/1 | NM_000525.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250858Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135664
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461726Hom.: 0 Cov.: 63 AF XY: 0.00000275 AC XY: 2AN XY: 727156
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 16, 2015 | This recessive mutation in the KCNJ11 gene was found in a case of congenital hyperinsulinemic hypoglycemia. The combination of this mutation with a second recessive mutation (c.154C>T) in the same gene explains the phenotype of this newborn patient. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1995 | - - |
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. However, no sufficient evidence is found to ascertain the role of this particular variant (rs28936678 ) in MODY yet. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;.
Vest4
MutPred
Loss of stability (P = 0.0083);.;.;
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