rs115466046

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_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. 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.62

Publications

25 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: G2P, Orphanet, Ambry Genetics, 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

KCNJ10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002241.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	NM_002241.5	MANE Select	c.53G>A	p.Arg18Gln	missense	Exon 2 of 2	NP_002232.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNJ10	ENST00000644903.1	MANE Select	c.53G>A	p.Arg18Gln	missense	Exon 2 of 2	ENSP00000495557.1	P78508
KCNJ10	ENST00000638728.1	TSL:5	c.53G>A	p.Arg18Gln	missense	Exon 3 of 3	ENSP00000492619.1	P78508
KCNJ10	ENST00000638868.1	TSL:5	c.53G>A	p.Arg18Gln	missense	Exon 3 of 3	ENSP00000491250.1	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

GnomAD2 exomes

AF:

0.0124

AC:

3115

AN:

251418

AF XY:

0.0129

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 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

African (AFR)

AF:

0.00218

AC:

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1232

2464

3695

4927

6159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.0108

AC:

1641

AN:

152250

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

771

AN XY:

74438

show subpopulations

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:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0106

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00924

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1179

AN:

68022

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

177

265

354

442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0157

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

EAST syndrome (2)

Autism;C0036572:Seizure;C3714756:Intellectual disability (1)

Inborn genetic diseases (1)

KCNJ10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

0.085

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.87

PhyloP100

1.6

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.13

REVEL

Benign

0.28

Sift

Benign

0.095

Sift4G

Uncertain

0.043

Polyphen

0.80

Vest4

0.029

MPC

0.70

ClinPred

0.014

GERP RS

5.2

PromoterAI

0.028

Neutral

(source)

Varity_R

0.13

gMVP

0.72

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over