rs138120505
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1
The NM_153766.3(KCNJ1):c.505C>T(p.Arg169Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,726 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_153766.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ1 | NM_153766.3 | c.505C>T | p.Arg169Cys | missense_variant | Exon 3 of 3 | ENST00000392666.6 | NP_722450.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000710 AC: 108AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000244 AC: 61AN: 249916Hom.: 0 AF XY: 0.000192 AC XY: 26AN XY: 135386
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461474Hom.: 0 Cov.: 33 AF XY: 0.0000729 AC XY: 53AN XY: 727012
GnomAD4 genome AF: 0.000742 AC: 113AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61AN XY: 74444
ClinVar
Submissions by phenotype
not specified Benign:2
Variant summary: KCNJ1 c.562C>T (p.Arg188Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 249916 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNJ1 causing Bartter Syndrome, Type 2 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.562C>T has been reported in the literature as a heterozygous non-informative (second allele not specified) genotype in at-least one individual of Congolese ethnic origin (African subcontinent) reportedly affected with neonatal Bartter Syndrome, Type 2 (example, Brochard_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Bartter Syndrome, Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
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Bartter disease type 2 Uncertain:1
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not provided Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 188 of the KCNJ1 protein (p.Arg188Cys). This variant is present in population databases (rs138120505, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of Bartter syndrome (PMID: 19096086). ClinVar contains an entry for this variant (Variation ID: 225398). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at