NM_002241.5:c.133G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_002241.5(KCNJ10):c.133G>A(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A45A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.29

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.117863566).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000752 (11/1461874) while in subpopulation AMR AF= 0.000246 (11/44724). AF 95% confidence interval is 0.000137. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. 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
KCNJ10	NM_002241.5 link	c.133G>A	p.Ala45Thr	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
KCNJ10	ENST00000644903.1 link	c.133G>A	p.Ala45Thr	missense_variant	Exon 2 of 2		NM_002241.5	ENSP00000495557.1		P78508

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251156

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

EAST syndrome

Uncertain:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 45 of the KCNJ10 protein (p.Ala45Thr). This variant is present in population databases (rs750246232, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with KCNJ10-related conditions. ClinVar contains an entry for this variant (Variation ID: 470191). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNJ10 protein function with a negative predictive value of 95%. 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. -

Apr 26, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 24, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A45T variant (also known as c.133G>A), located in coding exon 1 of the KCNJ10 gene, results from a G to A substitution at nucleotide position 133. The alanine at codon 45 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

KCNJ10-related disorder

Uncertain:1

Jun 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNJ10 c.133G>A variant is predicted to result in the amino acid substitution p.Ala45Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-160012190-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Jan 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

May 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

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

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.023

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.8

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

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.62

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

REVEL

Uncertain

0.37

Sift

Benign

0.43

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

Sift4G

Benign

0.56

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

Polyphen

0.0010

.;.;B;B;.;B;B

Vest4

0.066

MutPred

0.34

Gain of phosphorylation at A45 (P = 0.0514);Gain of phosphorylation at A45 (P = 0.0514);Gain of phosphorylation at A45 (P = 0.0514);Gain of phosphorylation at A45 (P = 0.0514);.;Gain of phosphorylation at A45 (P = 0.0514);Gain of phosphorylation at A45 (P = 0.0514);

MVP

0.84

MPC

0.51

ClinPred

0.081

GERP RS

5.2

Varity_R

0.19

gMVP

0.77

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