chr1-160041490-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

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. 13/22 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. R348C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:1

Conservation

PhyloP100: 0.953

Publications

13 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 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=0.06418976).
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000302 (46/152274) while in subpopulation NFE AF = 0.0005 (34/68010). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNJ10NM_002241.5 linkc.1043G>A p.Arg348His missense_variant Exon 2 of 2 ENST00000644903.1 NP_002232.2 P78508

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNJ10ENST00000644903.1 linkc.1043G>A p.Arg348His missense_variant Exon 2 of 2 NM_002241.5 ENSP00000495557.1 P78508

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152156
Hom.:
0
Cov.:
32
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
GnomAD2 exomes
AF:
0.000398
AC:
100
AN:
251396
AF XY:
0.000486
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 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.:
0
Cov.:
31
AF XY:
0.000418
AC XY:
304
AN XY:
727240
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33480
American (AMR)
AF:
0.000492
AC:
22
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000153
AC:
4
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86254
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53420
Middle Eastern (MID)
AF:
0.000694
AC:
4
AN:
5766
European-Non Finnish (NFE)
AF:
0.000511
AC:
568
AN:
1112002
Other (OTH)
AF:
0.000315
AC:
19
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
42
84
127
169
211
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
22
44
66
88
110
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.000295
AC XY:
22
AN XY:
74466
show subpopulations
African (AFR)
AF:
0.000120
AC:
5
AN:
41554
American (AMR)
AF:
0.000327
AC:
5
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000500
AC:
34
AN:
68010
Other (OTH)
AF:
0.000473
AC:
1
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.516
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000611
Hom.:
0
Bravo
AF:
0.000317
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000362
AC:
44
EpiCase
AF:
0.00104
EpiControl
AF:
0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:15Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:6
Jan 13, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 06, 2018
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

KCNJ10: PM2, PM5:Supporting, PS3:Supporting -

Pendred syndrome;C2748572:EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Uncertain:2
Feb 09, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Uncertain:2
-
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

May 02, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

EAST syndrome Uncertain:1Benign:1
Apr 28, 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). 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. -

Jan 25, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Mar 09, 2020
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Uncertain:1
May 10, 2019
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Apr 28, 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). 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. -

Intellectual disability Uncertain:1
Jan 01, 2019
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
18
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
N
LIST_S2
Benign
0.78
.;.;.;T
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.064
T;T;T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
1.6
L;L;L;L
PhyloP100
0.95
PrimateAI
Uncertain
0.50
T
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
T
GERP RS
4.2
PromoterAI
-0.013
Neutral
Varity_R
0.039
gMVP
0.40
Mutation Taster
=66/34
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

Publications

Other links and lift over

dbSNP: rs146396982; hg19: chr1-160011280; API