rs137853072
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_002241.5(KCNJ10):c.229G>C(p.Gly77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
Consequence
KCNJ10
NM_002241.5 missense
NM_002241.5 missense
Scores
7
5
1
Clinical Significance
Conservation
PhyloP100: 2.29
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002241.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
?
Variant 1-160042304-C-G is Pathogenic according to our data. Variant chr1-160042304-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7468.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-160042304-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ10 | NM_002241.5 | c.229G>C | p.Gly77Arg | missense_variant | 2/2 | ENST00000644903.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ10 | ENST00000644903.1 | c.229G>C | p.Gly77Arg | missense_variant | 2/2 | NM_002241.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
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
EAST syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the KCNJ10 protein (p.Gly77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SeSAME syndrome (PMID: 19420365). ClinVar contains an entry for this variant (Variation ID: 7468). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 19420365, 20807765, 21088294). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 12, 2010 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
Polyphen
0.99
.;.;D;D;.;D;D
Vest4
0.89
MutPred
Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);.;Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);
MVP
0.99
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at