rs141553756
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_002241.5(KCNJ10):c.136G>A(p.Asp46Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,614,156 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: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 1 hom. )
Consequence
KCNJ10
NM_002241.5 missense
NM_002241.5 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 3.25
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 Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011291474).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0013 (198/152296) while in subpopulation AFR AF= 0.0045 (187/41558). AF 95% confidence interval is 0.00397. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ10 | NM_002241.5 | c.136G>A | p.Asp46Asn | missense_variant | 2/2 | ENST00000644903.1 | NP_002232.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNJ10 | ENST00000644903.1 | c.136G>A | p.Asp46Asn | missense_variant | 2/2 | NM_002241.5 | ENSP00000495557 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00130 AC: 198AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000267 AC: 67AN: 251122Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135710
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GnomAD4 exome AF: 0.000116 AC: 170AN: 1461860Hom.: 1 Cov.: 32 AF XY: 0.000103 AC XY: 75AN XY: 727226
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GnomAD4 genome AF: 0.00130 AC: 198AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
EAST syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 22, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 13, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 14, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2016 | A variant of uncertain significance has been identified in the KCNJ10 gene. The D46N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D46N variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project but the 1000 Genomes Project reports it was observed in 2/1322 (0.2%) alleles from individuals of African background. The D46N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2018 | The p.D46N variant (also known as c.136G>A), located in coding exon 1 of the KCNJ10 gene, results from a G to A substitution at nucleotide position 136. The aspartic acid at codon 46 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
KCNJ10-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 14, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;T;T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;L;L;.;L;L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;N;.;.;.
REVEL
Uncertain
Sift
Benign
.;.;.;T;.;.;.
Sift4G
Benign
.;.;.;T;.;.;.
Polyphen
0.95
.;.;P;P;.;P;P
Vest4
0.35
MVP
0.66
MPC
0.91
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