rs115466046

Positions:

chr1-160042480-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_002241.5(KCNJ10):c.53G>A(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,106 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 9 hom., cov: 32)

Exomes 𝑓: 0.015 ( 191 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.62

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]

KCNJ10 links:

KCNJ10 (HGNC:):

KCNJ10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 63) in uniprot entity KCJ10_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_002241.5

BP4

Computational evidence support a benign effect (MetaRNN=0.006738782).

BP6

Variant 1-160042480-C-T is Benign according to our data. Variant chr1-160042480-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129316.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=7}. Variant chr1-160042480-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0108 (1641/152250) while in subpopulation NFE AF= 0.0173 (1179/68022). AF 95% confidence interval is 0.0165. There are 9 homozygotes in gnomad4. There are 771 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ10	NM_002241.5 linkuse as main transcript	c.53G>A	p.Arg18Gln	missense_variant	2/2	ENST00000644903.1	NP_002232.2	P78508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ10	ENST00000644903.1 linkuse as main transcript	c.53G>A	p.Arg18Gln	missense_variant	2/2		NM_002241.5	ENSP00000495557.1		P78508

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1642

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.00924

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.0124

AC:

3115

AN:

251418

Hom.:

AF XY:

0.0129

AC XY:

1748

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00656

Gnomad ASJ exome

AF:

0.00953

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0151

AC:

22033

AN:

1461856

Hom.:

191

Cov.:

AF XY:

0.0153

AC XY:

11095

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00218

Gnomad4 AMR exome

AF:

0.00653

Gnomad4 ASJ exome

AF:

0.00903

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0118

GnomAD4 genome

AF:

0.0108

AC:

1641

AN:

152250

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

771

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.00883

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.00924

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.00968

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0172

AC:

148

ExAC

AF:

0.0127

AC:

1545

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	This variant is associated with the following publications: (PMID: 27535533, 24794859, 21458570, 27884173, 27677466) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KCNJ10: BS1, BS2 -

EAST syndrome

Uncertain:1Benign: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). 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autism;C0036572:Seizure;C3714756:Intellectual disability

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg18Gln variant in KCNJ10 has been identified in 2 individuals with autism, seizures, and intellectual disability and segregated with disease in 2 relatives from 1 family (PMID: 21458570). This variant has also been identified in >1% of European (non-Finnish) chromosomes and 11 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg18Gln variant may not impact protein function (PMID: 21458570). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autism, seizures, and intellectual disability. -

KCNJ10-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2024

This variant is classified as 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

0.081

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;.;T;T;.;T;T

Eigen

Benign

0.085

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

T;T;.;.;T;.;T

MetaRNN

Benign

0.0067

T;T;T;T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.87

.;.;L;L;.;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.13

.;.;.;N;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.095

.;.;.;T;.;.;.

Sift4G

Uncertain

0.043

.;.;.;D;.;.;.

Polyphen

0.80

.;.;P;P;.;P;P

Vest4

0.029

MPC

0.70

ClinPred

0.014

GERP RS

5.2

Varity_R

0.13

gMVP

0.72

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over