NM_002241.5:c.53G>A

Variant names:

• chr1-160042480-C-T
• rs115466046
• NM_002241.5:c.53G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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. 14/21 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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (9 hom., cov: 32)
  • Exomes 𝑓: 0.015 (191 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.62
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• EAST syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• enlarged vestibular aqueduct syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 2.7053 (below the threshold of 3.09). GenCC associations: The gene is linked to EAST syndrome, enlarged vestibular aqueduct syndrome, Pendred syndrome.
• 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 VariationId is 129316.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ10	NM_002241.5	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 2	ENST00000644903.1	NP_002232.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ10	ENST00000644903.1	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 2		NM_002241.5	ENSP00000495557.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1642 AN: 152132 Hom.: 9 Cov.: 32

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

GnomAD2 exomes AF: 0.0124 AC: 3115 AN: 251418 AF XY: 0.0129

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 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.: 32 AF XY: 0.0153 AC XY: 11095 AN XY: 727238

African (AFR) AF: 0.00218 AC: 73 AN: 33480

American (AMR) AF: 0.00653 AC: 292 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00903 AC: 236 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0121 AC: 1041 AN: 86256

European-Finnish (FIN) AF: 0.0120 AC: 642 AN: 53408

Middle Eastern (MID) AF: 0.0241 AC: 139 AN: 5768

European-Non Finnish (NFE) AF: 0.0170 AC: 18895 AN: 1111990

Other (OTH) AF: 0.0118 AC: 714 AN: 60394

GnomAD4 genome AF: 0.0108 AC: 1641 AN: 152250 Hom.: 9 Cov.: 32 AF XY: 0.0104 AC XY: 771 AN XY: 74438

African (AFR) AF: 0.00296 AC: 123 AN: 41558

American (AMR) AF: 0.00883 AC: 135 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4818

European-Finnish (FIN) AF: 0.00924 AC: 98 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1179 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0157 Hom.: 61

Bravo AF: 0.00968

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0172 AC: 148

ExAC AF: 0.0127 AC: 1545

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Mar 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Aug 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNJ10: BS1, BS2 -

Nov 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27535533, 24794859, 21458570, 27884173, 27677466) -

May 21, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EAST syndrome Uncertain:1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Mar 21, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Apr 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
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	D
LIST_S2	Benign	0.85	T;T;.;.;T;.;T
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.87	.;.;L;L;.;L;L
PhyloP100		1.6
PrimateAI	Uncertain	0.52	T
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	T
GERP RS		5.2
PromoterAI		0.028	Neutral
Varity_R		0.13
gMVP		0.72
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs115466046; hg19: chr1-160012270; COSMIC: COSV99058500; COSMIC: COSV99058500;