chr11-128912117-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000890.5(KCNJ5):c.844C>G(p.Gln282Glu) variant causes a missense change. The variant allele was found at a frequency of 0.985 in 1,613,492 control chromosomes in the GnomAD database, including 782,184 homozygotes. 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q282K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.99 ( 74347 hom., cov: 33)

Exomes 𝑓: 0.98 ( 707837 hom. )

Consequence

KCNJ5
NM_000890.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.89

Publications

47 publications found

Variant links:

Genes affected

KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

KCNJ5 Gene-Disease associations (from GenCC):

familial hyperaldosteronism type III
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Andersen-Tawil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
long QT syndrome 13
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNJ5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.373099E-7).

BP6

Variant 11-128912117-C-G is Benign according to our data. Variant chr11-128912117-C-G is described in ClinVar as Benign. ClinVar VariationId is 137993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5 link	c.844C>G	p.Gln282Glu	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.844C>G	p.Gln282Glu	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.844C>G	p.Gln282Glu	missense_variant	Exon 2 of 3		XP_011541112.1	P48544A0A5J6E2W8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNJ5	ENST00000529694.6 link	c.844C>G	p.Gln282Glu	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5	ENST00000338350.4 link	c.844C>G	p.Gln282Glu	missense_variant	Exon 3 of 4	1		ENSP00000339960.4	P48544
KCNJ5	ENST00000533599.1 link	c.844C>G	p.Gln282Glu	missense_variant	Exon 1 of 2	1		ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes

AF:

0.988

AC:

150349

AN:

152158

Hom.:

74287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.997

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.996

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

0.979

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

0.980

Gnomad OTH

AF:

0.994

GnomAD2 exomes

AF:

0.988

AC:

244884

AN:

247900

AF XY:

0.988

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

0.998

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.979

Gnomad NFE exome

AF:

0.979

Gnomad OTH exome

AF:

0.989

GnomAD4 exome

AF:

0.984

AC:

1438219

AN:

1461216

Hom.:

707837

Cov.:

AF XY:

0.985

AC XY:

715780

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.998

AC:

33407

AN:

33480

American (AMR)

AF:

0.997

AC:

44599

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.998

AC:

26081

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39697

AN:

39700

South Asian (SAS)

AF:

0.998

AC:

86099

AN:

86256

European-Finnish (FIN)

AF:

0.977

AC:

51601

AN:

52820

Middle Eastern (MID)

AF:

0.999

AC:

5765

AN:

5768

European-Non Finnish (NFE)

AF:

0.981

AC:

1091323

AN:

1111950

Other (OTH)

AF:

0.988

AC:

59647

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1252

2504

3756

5008

6260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21664

43328

64992

86656

108320

<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:

0.988

AC:

150468

AN:

152276

Hom.:

74347

Cov.:

AF XY:

0.989

AC XY:

73610

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.997

AC:

41443

AN:

41560

American (AMR)

AF:

0.996

AC:

15244

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

3467

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5167

AN:

5168

South Asian (SAS)

AF:

0.998

AC:

4820

AN:

4830

European-Finnish (FIN)

AF:

0.979

AC:

10387

AN:

10612

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

0.980

AC:

66636

AN:

68002

Other (OTH)

AF:

0.994

AC:

2102

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.982

Hom.:

18447

Bravo

AF:

0.990

TwinsUK

AF:

0.981

AC:

3638

ALSPAC

AF:

0.981

AC:

3780

ESP6500AA

AF:

0.997

AC:

4389

ESP6500EA

AF:

0.982

AC:

8439

ExAC

AF:

0.986

AC:

119721

Asia WGS

AF:

0.998

AC:

3472

AN:

3478

EpiCase

AF:

0.984

EpiControl

AF:

0.984

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2013

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

- -

Familial hyperaldosteronism type III

Benign:2

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. -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome 13

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KCNJ5-related disorder

Benign:1

Mar 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital long QT syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.40

DEOGEN2

Uncertain

0.51

D;D;D

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.25

.;.;T

MetaRNN

Benign

8.4e-7

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.5

N;N;N

PhyloP100

5.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

1.1

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.018

MPC

0.44

ClinPred

0.0039

GERP RS

5.5

Varity_R

0.17

gMVP

0.54

Mutation Taster

=97/3

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