11-128912217-C-T

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.937+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,597,078 control chromosomes in the GnomAD database, including 1,633 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.061 ( 712 hom., cov: 33)

Exomes 𝑓: 0.015 ( 921 hom. )

Consequence

KCNJ5
NM_000890.5 splice_region, intron

Scores

Splicing: ADA: 0.00006703

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.761

Publications

4 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 (BayesDel_noAF=-0.82).

BP6

Variant 11-128912217-C-T is Benign according to our data. Variant chr11-128912217-C-T is described in ClinVar as Benign. ClinVar VariationId is 137994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KCNJ5	NM_000890.5 link	c.937+7C>T	splice_region_variant, intron_variant	Intron 2 of 2	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2 link	c.937+7C>T	splice_region_variant, intron_variant	Intron 3 of 3		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.937+7C>T	splice_region_variant, intron_variant	Intron 2 of 2		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
KCNJ5	ENST00000529694.6 link	c.937+7C>T	splice_region_variant, intron_variant	Intron 2 of 2	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4 link	c.937+7C>T	splice_region_variant, intron_variant	Intron 3 of 3	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1 link	c.937+7C>T	splice_region_variant, intron_variant	Intron 1 of 1	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes

AF:

0.0610

AC:

9283

AN:

152154

Hom.:

710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0415

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0896

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00814

Gnomad OTH

AF:

0.0602

GnomAD2 exomes

AF:

0.0299

AC:

7012

AN:

234546

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.183

Gnomad AMR exome

AF:

0.0220

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.0907

Gnomad FIN exome

AF:

0.00692

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.0280

GnomAD4 exome

AF:

0.0151

AC:

21806

AN:

1444806

Hom.:

921

Cov.:

AF XY:

0.0143

AC XY:

10302

AN XY:

719400

show subpopulations

African (AFR)

AF:

0.186

AC:

6219

AN:

33374

American (AMR)

AF:

0.0249

AC:

1114

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

389

AN:

26114

East Asian (EAS)

AF:

0.0756

AC:

2999

AN:

39676

South Asian (SAS)

AF:

0.00843

AC:

726

AN:

86170

European-Finnish (FIN)

AF:

0.00659

AC:

264

AN:

40060

Middle Eastern (MID)

AF:

0.0349

AC:

187

AN:

5352

European-Non Finnish (NFE)

AF:

0.00715

AC:

7929

AN:

1109198

Other (OTH)

AF:

0.0329

AC:

1979

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1031

2062

3094

4125

5156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.0611

AC:

9300

AN:

152272

Hom.:

712

Cov.:

AF XY:

0.0592

AC XY:

4411

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.176

AC:

7326

AN:

41536

American (AMR)

AF:

0.0413

AC:

632

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.0898

AC:

465

AN:

5176

South Asian (SAS)

AF:

0.0127

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00814

AC:

554

AN:

68028

Other (OTH)

AF:

0.0601

AC:

127

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

420

839

1259

1678

2098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0340

Hom.:

517

Bravo

AF:

0.0706

EpiCase

AF:

0.00856

EpiControl

AF:

0.0100

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 10, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2014

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. -

Clinical Genetics, Academic Medical Center

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial hyperaldosteronism type III

Benign:1

Jan 12, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.82

(source)

DANN

Benign

0.36

PhyloP100

-0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000067

dbscSNV1_RF

Benign

0.0

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

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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