11-128912107-T-C

Variant names:

Variant summary

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

The NM_000890.5(KCNJ5):c.834T>C(p.His278His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,613,232 control chromosomes in the GnomAD database, including 549,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 54483 hom., cov: 33)

Exomes 𝑓: 0.82 ( 495084 hom. )

Consequence

KCNJ5
NM_000890.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.09

Publications

25 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 11-128912107-T-C is Benign according to our data. Variant chr11-128912107-T-C is described in ClinVar as Benign. ClinVar VariationId is 137992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNJ5	NM_000890.5 link	c.834T>C	p.His278His	synonymous_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2 link	c.834T>C	p.His278His	synonymous_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.834T>C	p.His278His	synonymous_variant	Exon 2 of 3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNJ5	ENST00000529694.6 link	c.834T>C	p.His278His	synonymous_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4 link	c.834T>C	p.His278His	synonymous_variant	Exon 3 of 4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1 link	c.834T>C	p.His278His	synonymous_variant	Exon 1 of 2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes

AF:

0.845

AC:

128469

AN:

152012

Hom.:

54439

Cov.:

show subpopulations

Gnomad AFR

AF:

0.895

Gnomad AMI

AF:

0.865

Gnomad AMR

AF:

0.837

Gnomad ASJ

AF:

0.841

Gnomad EAS

AF:

0.879

Gnomad SAS

AF:

0.893

Gnomad FIN

AF:

0.795

Gnomad MID

AF:

0.826

Gnomad NFE

AF:

0.818

Gnomad OTH

AF:

0.858

GnomAD2 exomes

AF:

0.839

AC:

208357

AN:

248472

AF XY:

0.842

show subpopulations

Gnomad AFR exome

AF:

0.898

Gnomad AMR exome

AF:

0.814

Gnomad ASJ exome

AF:

0.848

Gnomad EAS exome

AF:

0.880

Gnomad FIN exome

AF:

0.793

Gnomad NFE exome

AF:

0.824

Gnomad OTH exome

AF:

0.836

GnomAD4 exome

AF:

0.823

AC:

1201885

AN:

1461102

Hom.:

495084

Cov.:

AF XY:

0.826

AC XY:

600301

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.903

AC:

30216

AN:

33476

American (AMR)

AF:

0.813

AC:

36355

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.847

AC:

22145

AN:

26134

East Asian (EAS)

AF:

0.872

AC:

34631

AN:

39700

South Asian (SAS)

AF:

0.890

AC:

76739

AN:

86254

European-Finnish (FIN)

AF:

0.789

AC:

41827

AN:

52988

Middle Eastern (MID)

AF:

0.885

AC:

5107

AN:

5768

European-Non Finnish (NFE)

AF:

0.814

AC:

904835

AN:

1111684

Other (OTH)

AF:

0.829

AC:

50030

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

12371

24742

37114

49485

61856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20908

41816

62724

83632

104540

<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:

0.845

AC:

128568

AN:

152130

Hom.:

54483

Cov.:

AF XY:

0.846

AC XY:

62918

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.895

AC:

37157

AN:

41508

American (AMR)

AF:

0.837

AC:

12799

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.841

AC:

2916

AN:

3466

East Asian (EAS)

AF:

0.880

AC:

4541

AN:

5162

South Asian (SAS)

AF:

0.893

AC:

4309

AN:

4826

European-Finnish (FIN)

AF:

0.795

AC:

8429

AN:

10596

Middle Eastern (MID)

AF:

0.823

AC:

242

AN:

294

European-Non Finnish (NFE)

AF:

0.818

AC:

55571

AN:

67958

Other (OTH)

AF:

0.858

AC:

1815

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1048

2096

3143

4191

5239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.828

Hom.:

19455

Bravo

AF:

0.849

Asia WGS

AF:

0.883

AC:

3065

AN:

3474

EpiCase

AF:

0.833

EpiControl

AF:

0.833

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

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

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

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.72

(source)

DANN

Benign

0.58

PhyloP100

-1.1

Mutation Taster

=93/7

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