rs117808169
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_004982.4(KCNJ8):āc.263C>Gā(p.Ala88Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,614,240 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00020 ( 0 hom., cov: 33)
Exomes š: 0.00025 ( 1 hom. )
Consequence
KCNJ8
NM_004982.4 missense
NM_004982.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
KCNJ8 (HGNC:6269): (potassium inwardly rectifying channel subfamily J member 8) 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. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNJ8. . Gene score misZ 3.4549 (greater than the threshold 3.09). Trascript score misZ 4.3809 (greater than threshold 3.09). GenCC has associacion of gene with hypertrichotic osteochondrodysplasia Cantu type, Brugada syndrome, Brugada syndrome 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.23628831).
BP6
Variant 12-21773354-G-C is Benign according to our data. Variant chr12-21773354-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190832.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr12-21773354-G-C is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 31 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ8 | NM_004982.4 | c.263C>G | p.Ala88Gly | missense_variant | 2/3 | ENST00000240662.3 | NP_004973.1 | |
LOC105369689 | XR_007063241.1 | n.631+13269G>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNJ8 | ENST00000240662.3 | c.263C>G | p.Ala88Gly | missense_variant | 2/3 | 1 | NM_004982.4 | ENSP00000240662.2 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000302 AC: 76AN: 251486Hom.: 0 AF XY: 0.000375 AC XY: 51AN XY: 135914
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GnomAD4 exome AF: 0.000254 AC: 371AN: 1461890Hom.: 1 Cov.: 31 AF XY: 0.000287 AC XY: 209AN XY: 727246
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GnomAD4 genome AF: 0.000203 AC: 31AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74504
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2022 | Reported in a patient with atrioventricular nodal re-entrant tachycardia and concealed Brugada sign on ECG (Hasdemir et al., 2015); Identified independently and in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data are absent at this time; In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 25998140) - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 88 of the KCNJ8 protein (p.Ala88Gly). This variant is present in population databases (rs117808169, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with KCNJ8-related conditions (PMID: 25998140, 28750076). ClinVar contains an entry for this variant (Variation ID: 190832). 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 not expected to disrupt KCNJ8 protein function with a negative predictive value of 80%. 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. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: BS1, PP2 - |
Syndromic disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Limited evidence for a gene-disease association, with few variants reported and with conflicting conclusions. (I) 0107 - This gene is associated with autosomal dominant disease. Limited evidence for a gene-disease association, with few variants reported. There is no disease associated with this gene in OMIM. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2.1.1) <0.001 for a dominant condition. 0.000286 (81 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, high conservation. (I) 0600 - Variant is located in the Inward rectifier potassium channel transmembrane domain (DECIPHER, RCSB PDB, NCBI_Conserved domains). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: VUSx2, LOVD3: Likely benign x1. PMID: 25998140: A patient with atrioventricular nodal re-entrant tachycardia (AVNT) and concealed Brugada syndrome. PMID: 28750076: A patient with HCM who also had a pathogenic variant in MYBPC3 and several other variants in other cardiac genes. At VCGS, in a patient who had a cardiac arrest and a diagnosis of LQTS. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) ā Information, (SB) ā Supporting Benign - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
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