rs137853067
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_002241.5(KCNJ10):c.595C>T(p.Arg199Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,174 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KCNJ10
NM_002241.5 stop_gained
NM_002241.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 5.49
Genes affected
KCNJ10 (HGNC:6256): (potassium inwardly rectifying channel subfamily J member 10) This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-160041938-G-A is Pathogenic according to our data. Variant chr1-160041938-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160041938-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ10 | NM_002241.5 | c.595C>T | p.Arg199Ter | stop_gained | 2/2 | ENST00000644903.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ10 | ENST00000644903.1 | c.595C>T | p.Arg199Ter | stop_gained | 2/2 | NM_002241.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726190
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
EAST syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 10, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 21, 2023 | This sequence change creates a premature translational stop signal (p.Arg199*) in the KCNJ10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 181 amino acid(s) of the KCNJ10 protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects KCNJ10 function (PMID: 20651251, 20678478, 20807765, 21088294). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 7463). This premature translational stop signal has been observed in individual(s) with seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) (PMID: 19289823, 23924083). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | The homozygous p.Arg199Ter variant in KCNJ10 was identified by our study in one individual with EAST syndrome. The p.Arg199Ter variant in KCNJ10 has been reported in one individual with EAST syndrome (PMID: 19289823). This individual was a compound heterozygote who carried a likely pathogenic variant in trans (ClinVar Variation ID: 7462), which increases the likelihood that the p.Arg199Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7463) and has been interpreted as pathogenic by Invitae and OMIM. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg199Ter variant may impact protein function (PMID: 20651251). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 199. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the KCNJ10 gene is strongly associated to autosomal recessive EAST syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive EAST syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PS3_Supporting, PM3 (Richards 2015). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2022 | Published functional studies demonstrate that the variant causes loss of protein function as well as lack of cell surface protein expression (Tang et al., 2010; Reichold et al., 2010); Nonsense variant predicted to result in protein truncation as the last 181 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20807765, 21088294, 33996354, 34638578, 21849804, 26961251, 24480364, 28835827, 27129733, 22809040, 23922547, 27500072, 28520217, 30952461, 29722316, 20651251, 26147798, 29358904, 23924083, 20678478, 29722015, 19289823) - |
Pendred syndrome;C2748572:EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
0.93
GERP RS
Splicing
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Calibrated prediction
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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