rs137853070

Positions:

chr1-160042033-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_002241.5(KCNJ10):c.500C>T(p.Ala167Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,560,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 8.09

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 Pathogenic. Variant got 14 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

PP5

Variant 1-160042033-G-A is Pathogenic according to our data. Variant chr1-160042033-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160042033-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ10	NM_002241.5 linkuse as main transcript	c.500C>T	p.Ala167Val	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.500C>T	p.Ala167Val	missense_variant	2/2		NM_002241.5	ENSP00000495557	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000958

AC:

AN:

208856

Hom.:

AF XY:

0.0000182

AC XY:

AN XY:

110102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000501

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1408446

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

693814

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

EAST syndrome

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 12, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2022	ClinVar contains an entry for this variant (Variation ID: 7466). This missense change has been observed in individual(s) with SeSAME syndrome (PMID: 19289823, 24193250). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs137853070, gnomAD 0.005%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 167 of the KCNJ10 protein (p.Ala167Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 20678478, 20807765, 21088294, 24561201). 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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely pathogenic and reported on 06/02/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2024

Published functional studies demonstrate a damaging effect resulting in a partial loss of KCNJ10 function (PMID: 20678478, 26867573); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20807765, 30356026, 29722316, 33424762, 34713909, 27129733, 21088294, 34638578, 24561201, 26867573, 26862828, 27500072, 21221631, 28747464, 33996354, 29666984, 32062759, 28835827, 21849804, 28520217, 24014171, 31731488, 30952461, 29722015, 19289823, 20678478, 24193250) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;.;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

.;.;D;.;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.0

M;M;.;M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.5

.;N;.;.;.

REVEL

Pathogenic

0.83

Sift

Benign

0.24

.;T;.;.;.

Sift4G

Benign

0.12

.;T;.;.;.

Polyphen

1.0

D;D;.;D;D

Vest4

0.91

MutPred

0.75

Loss of disorder (P = 0.0726);Loss of disorder (P = 0.0726);.;Loss of disorder (P = 0.0726);Loss of disorder (P = 0.0726);

MVP

0.97

MPC

1.5

ClinPred

0.84

GERP RS

5.4

Varity_R

0.44

gMVP

0.92

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