rs173135

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000891.3(KCNJ2):c.1146C>T(p.Leu382Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,708 control chromosomes in the GnomAD database, including 12,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1313 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10940 hom. )

Consequence

KCNJ2
NM_000891.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.32

Publications

25 publications found

Variant links:

Genes affected

KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

KCNJ2 Gene-Disease associations (from GenCC):

Andersen-Tawil syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
short QT syndrome type 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
short QT syndrome
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
long QT syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

KCNJ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 17-70176185-C-T is Benign according to our data. Variant chr17-70176185-C-T is described in ClinVar as Benign. ClinVar VariationId is 137988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ2	NM_000891.3 link	c.1146C>T	p.Leu382Leu	synonymous_variant	Exon 2 of 2	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 link	c.1146C>T	p.Leu382Leu	synonymous_variant	Exon 2 of 2	1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1 link	c.1146C>T	p.Leu382Leu	synonymous_variant	Exon 2 of 2	1		ENSP00000441848.1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19641

AN:

151876

Hom.:

1312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.140

GnomAD2 exomes

AF:

0.136

AC:

34181

AN:

250672

AF XY:

0.135

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.0903

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.121

AC:

176347

AN:

1461714

Hom.:

10940

Cov.:

AF XY:

0.121

AC XY:

87878

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.135

AC:

4523

AN:

33478

American (AMR)

AF:

0.224

AC:

9999

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

3216

AN:

26136

East Asian (EAS)

AF:

0.0992

AC:

3937

AN:

39698

South Asian (SAS)

AF:

0.159

AC:

13720

AN:

86256

European-Finnish (FIN)

AF:

0.0932

AC:

4970

AN:

53328

Middle Eastern (MID)

AF:

0.145

AC:

837

AN:

5768

European-Non Finnish (NFE)

AF:

0.115

AC:

127652

AN:

1111932

Other (OTH)

AF:

0.124

AC:

7493

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

9969

19937

29906

39874

49843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4756

9512

14268

19024

23780

<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:

0.129

AC:

19659

AN:

151994

Hom.:

1313

Cov.:

AF XY:

0.130

AC XY:

9641

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.139

AC:

5752

AN:

41430

American (AMR)

AF:

0.187

AC:

2855

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

453

AN:

3472

East Asian (EAS)

AF:

0.114

AC:

587

AN:

5142

South Asian (SAS)

AF:

0.165

AC:

795

AN:

4806

European-Finnish (FIN)

AF:

0.0924

AC:

977

AN:

10568

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7821

AN:

67978

Other (OTH)

AF:

0.138

AC:

291

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

851

1703

2554

3406

4257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.128

Hom.:

1235

Bravo

AF:

0.138

Asia WGS

AF:

0.124

AC:

432

AN:

3478

EpiCase

AF:

0.113

EpiControl

AF:

0.117

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 07, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Andersen Tawil syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Atrial fibrillation, familial, 9

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jun 24, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Short QT syndrome type 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.9

(source)

DANN

Benign

0.72

PhyloP100

1.3

Mutation Taster

=95/5

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over