1-160041490-C-T

Position:

chr1-160041490-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_Strong

The NM_002241.5(KCNJ10):c.1043G>A(p.Arg348His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 0.953

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 214) in uniprot entity KCJ10_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002241.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-160041491-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.06418976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ10	NM_002241.5 linkuse as main transcript	c.1043G>A	p.Arg348His	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 linkuse as main transcript	c.1043G>A	p.Arg348His	missense_variant	2/2		NM_002241.5	ENSP00000495557	P1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000398

AC:

100

AN:

251396

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000425

AC:

622

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

304

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000511

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000302

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000644

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	A variant of uncertain significance has been identified in the KCNJ10 gene. The R348H variant has been published as a non-synonymous SNP in a patient with congenital hyperinsulinism of infancy (Proverbio et al., 2013). Additionally, the R348H variant has been reported previously in a patient with epileptic spasms, severe intellectual disability, autism spectrum disorder, and EEG abnormalities as well as in her father who has EEG abnormalities and a severe anxiety disorder (Sicca et al., 2016). Functional studies suggest that the R348H variant may affect channel function (Sicca et al., 2016). A different amino acid substitution at the same position (R348C) was reported in a patient with enlarged vestibular aqueduct syndrome who also had a single pathogenic variant in the SLC26A4 gene (Yang et al., 2009). Of note, the patient's unaffected mother and unaffected sibling also had the R348C variant in the KCNJ10 gene (Yang et al., 2009). The R348H variant is observed in 37/66,576 (0.06%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R348H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -

EAST syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 348 of the KCNJ10 protein (p.Arg348His). This variant is present in population databases (rs146396982, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of KCNJ10-related conditions (PMID: 27677466). ClinVar contains an entry for this variant (Variation ID: 205823). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNJ10 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNJ10 function (PMID: 27677466). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 09, 2020

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2019

The p.R348H variant (also known as c.1043G>A), located in coding exon 1 of the KCNJ10 gene, results from a G to A substitution at nucleotide position 1043. The arginine at codon 348 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was reported in an individual with congenital hyperinsulinism of infancy (Proverbio MC et al. PLoS ONE, 2013 Jul;8:e68740). It was also detected in a child with epileptic spasms, intellectual disability, and autism as well as in her father who had severe anxiety disorder and focal abnormalities on EEG (Sicca F et al. Sci Rep, 2016 Sep;6:34325). In a child with infantile spasms, developmental delay, an abnormal EEG, left frontal lobe cortical dysplasia, hypotonia, and brachycephaly, this variant co-occurred with an apparently de novo SCN8A pathogenic mutation (Butler KM et al. Epilepsy Res., 2017 01;129:17-25). Of note, none of the four aforementioned individuals were found to carry a second KCNJ10 alteration. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, 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 28, 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. -

Pendred syndrome;C2748572:EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

KCNJ10 NM_002241.4 exon 2 p.Arg348His (c.1043G>A): This variant has been reported in the literature in 1 individual with congenital hyperinsulinism of infancy (CHI) (Proverbio 2013 PMID:23869231), as well as in 1 individual with autism and epilepsy, segregating with disease in 1 affected relative (Sicca 2016 PMID:7677466). This variant is present in 83/126554 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs146396982). This variant is present in ClinVar (Variation ID:205823). Evolutionary conservation and computational predictive tools for this variant are unclear. Zebrafish and patch-clamp functional studies suggest a deleterious effect of this variant; however, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.16

T;T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.78

.;.;.;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.064

T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.6

L;L;L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.54

.;N;.;.

REVEL

Uncertain

0.30

Sift

Benign

0.14

.;T;.;.

Sift4G

Benign

0.14

.;T;.;.

Polyphen

0.024

B;B;B;B

Vest4

0.20

MVP

0.70

MPC

1.0

ClinPred

0.022

GERP RS

4.2

Varity_R

0.039

gMVP

0.40

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