rs864622292
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3PP5_Moderate
The NM_000891.3(KCNJ2):c.407_409delinsTTT(p.Ser136_Ile137delinsPhePhe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
KCNJ2
NM_000891.3 missense
NM_000891.3 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) 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, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000891.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, KCNJ2
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 17-70175446-CCA-TTT is Pathogenic according to our data. Variant chr17-70175446-CCA-TTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219878.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.407_409delinsTTT | p.Ser136_Ile137delinsPhePhe | missense_variant | 2/2 | ENST00000243457.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ2 | ENST00000243457.4 | c.407_409delinsTTT | p.Ser136_Ile137delinsPhePhe | missense_variant | 2/2 | 1 | NM_000891.3 | P1 | |
KCNJ2 | ENST00000535240.1 | c.407_409delinsTTT | p.Ser136_Ile137delinsPhePhe | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2016 | This variant, c.407_409delCCAinsTTT, is a complex sequence change that results in the deletion of 2 amino acids  (Ser and Ile) and the insertion of 2 amino acids (Phe and Phe) to the KCNJ2 protein (p.Ser136_Ile137delinsPhePhe), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases and has not been published in the literature. This sequence change introduces two phenylalanine residues at the p.136 and p.137 codons. A missense substitution which introduces one phenylalanine at this position (p.Ser136Phe) has been reported in an individual affected with Andersen-Tawil syndrome and has been shown to be deleterious by causing a dominant negative effect (PMID: 11371347, 12163457, 12909315, 14522976, 22002906). These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. In summary, this is a novel in-frame sequence change which affects an important residue required for KCNJ2 protein function. For these reasons, this variant has been classified as Likely Pathogenic. - |
Andersen Tawil syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2016 | This variant, c.407_409delCCAinsTTT, is a complex sequence change that results in the deletion of 2 amino acids (Ser and Ile) and the insertion of 2 amino acids (Phe and Phe) to the KCNJ2 protein (p.Ser136_Ile137delinsPhePhe), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases and has not been published in the literature. This sequence change introduces two phenylalanine residues at the p.136 and p.137 codons. A missense substitution which introduces one phenylalanine at this position (p.Ser136Phe) has been reported in an individual affected with Andersen-Tawil syndrome and has been shown to be deleterious by causing a dominant negative effect (PMID: 11371347, 12163457, 12909315, 14522976, 22002906). These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. In summary, this is a novel in-frame sequence change which affects an important residue required for KCNJ2 protein function. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at