rs141553756

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

Scores

9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 3.25
Variant links:
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 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
KCNJ10NM_002241.5 linkuse as main transcriptc.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
KCNJ10ENST00000644903.1 linkuse as main transcriptc.136G>A p.Asp46Asn missense_variant 2/2 NM_002241.5 ENSP00000495557 P1

Frequencies

GnomAD3 genomes
AF:
0.00130
AC:
198
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00451
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000267
AC:
67
AN:
251122
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.00370
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000116
AC:
170
AN:
1461860
Hom.:
1
Cov.:
32
AF XY:
0.000103
AC XY:
75
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00418
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.00130
AC:
198
AN:
152296
Hom.:
0
Cov.:
32
AF XY:
0.00134
AC XY:
100
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00450
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000278
Hom.:
0
Bravo
AF:
0.00155
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000371
AC:
45
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 submitterclinical testingNew York Genome CenterDec 22, 2021- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 13, 2017This 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 submitterclinical testingEurofins Ntd Llc (ga)May 18, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsAug 14, 2018- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 30, 2016A 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 submitterclinical testingAmbry GeneticsJun 12, 2018The 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 providedclinical testingPreventionGenetics, part of Exact SciencesSep 14, 2020This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
.;.;T;T;.;T;T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D;D;.;.;D;.;D
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.011
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.15
D
MutationAssessor
Benign
1.0
.;.;L;L;.;L;L
MutationTaster
Benign
0.99
D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-0.18
.;.;.;N;.;.;.
REVEL
Uncertain
0.32
Sift
Benign
0.59
.;.;.;T;.;.;.
Sift4G
Benign
0.43
.;.;.;T;.;.;.
Polyphen
0.95
.;.;P;P;.;P;P
Vest4
0.35
MVP
0.66
MPC
0.91
ClinPred
0.058
T
GERP RS
5.2
Varity_R
0.23
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141553756; hg19: chr1-160012187; COSMIC: COSV100927870; COSMIC: COSV100927870; API