rs1130183

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002241.5(KCNJ10):c.811C>T(p.Arg271Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,614,064 control chromosomes in the GnomAD database, including 3,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.046 ( 241 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3320 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.19

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033473969).

BP6

Variant 1-160041722-G-A is Benign according to our data. Variant chr1-160041722-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160041722-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ10	NM_002241.5 linkuse as main transcript	c.811C>T	p.Arg271Cys	missense_variant	2/2	ENST00000644903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ10	ENST00000644903.1 linkuse as main transcript	c.811C>T	p.Arg271Cys	missense_variant	2/2		NM_002241.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0460

AC:

6997

AN:

152088

Hom.:

242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.0357

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0780

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0702

Gnomad OTH

AF:

0.0388

GnomAD3 exomes

AF:

0.0458

AC:

11513

AN:

251402

Hom.:

407

AF XY:

0.0455

AC XY:

6188

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.0788

Gnomad NFE exome

AF:

0.0690

Gnomad OTH exome

AF:

0.0442

GnomAD4 exome

AF:

0.0628

AC:

91736

AN:

1461858

Hom.:

3320

Cov.:

AF XY:

0.0615

AC XY:

44739

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00968

Gnomad4 AMR exome

AF:

0.0255

Gnomad4 ASJ exome

AF:

0.0210

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0160

Gnomad4 FIN exome

AF:

0.0798

Gnomad4 NFE exome

AF:

0.0730

Gnomad4 OTH exome

AF:

0.0473

GnomAD4 genome

AF:

0.0460

AC:

6995

AN:

152206

Hom.:

241

Cov.:

AF XY:

0.0452

AC XY:

3363

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0117

Gnomad4 AMR

AF:

0.0356

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.0780

Gnomad4 NFE

AF:

0.0702

Gnomad4 OTH

AF:

0.0384

Alfa

AF:

0.0591

Hom.:

746

Bravo

AF:

0.0400

TwinsUK

AF:

0.0734

AC:

272

ALSPAC

AF:

0.0714

AC:

275

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.0655

AC:

563

ExAC

AF:

0.0457

AC:

5545

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0609

EpiControl

AF:

0.0585

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

EAST syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.20

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.0033

T;T;T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

1.5

L;L;L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

Polyphen

1.0

D;D;D;D

Vest4

0.14

MPC

1.5

ClinPred

0.021

GERP RS

5.4

Varity_R

0.34

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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