11-128912117-C-G

Position:

chr11-128912117-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 233) in uniprot entity KCNJ5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000890.5

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 id is 137993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-128912117-C-G is described in Lovd as [Benign].

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/exons	MANE	Protein
KCNJ5	NM_000890.5 linkuse as main transcript	c.844C>G	p.Gln282Glu	missense_variant	2/3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2 linkuse as main transcript	c.844C>G	p.Gln282Glu	missense_variant	3/4		NP_001341098.1
KCNJ5	XM_011542810.4 linkuse as main transcript	c.844C>G	p.Gln282Glu	missense_variant	2/3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KCNJ5	ENST00000529694.6 linkuse as main transcript	c.844C>G	p.Gln282Glu	missense_variant	2/3	1	NM_000890.5	ENSP00000433295	P1
KCNJ5	ENST00000338350.4 linkuse as main transcript	c.844C>G	p.Gln282Glu	missense_variant	3/4	1		ENSP00000339960	P1
KCNJ5	ENST00000533599.1 linkuse as main transcript	c.844C>G	p.Gln282Glu	missense_variant	1/2	1		ENSP00000434266	P1

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

GnomAD3 exomes

AF:

0.988

AC:

244884

AN:

247900

Hom.:

120972

AF XY:

0.988

AC XY:

132507

AN XY:

134138

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 SAS exome

AF:

0.998

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

Gnomad4 AFR exome

AF:

0.998

Gnomad4 AMR exome

AF:

0.997

Gnomad4 ASJ exome

AF:

0.998

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.998

Gnomad4 FIN exome

AF:

0.977

Gnomad4 NFE exome

AF:

0.981

Gnomad4 OTH exome

AF:

0.988

GnomAD4 genome

AF:

0.988

AC:

150468

AN:

152276

Hom.:

74347

Cov.:

AF XY:

0.989

AC XY:

73610

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.997

Gnomad4 AMR

AF:

0.996

Gnomad4 ASJ

AF:

0.999

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.998

Gnomad4 FIN

AF:

0.979

Gnomad4 NFE

AF:

0.980

Gnomad4 OTH

AF:

0.994

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

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial hyperaldosteronism type III

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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. -

Long QT syndrome 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

KCNJ5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Congenital long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2015

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

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

MutationTaster

Benign

1.0

P;P;P

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

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

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