rs387906778

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000890.5(KCNJ5):c.472A>G(p.Thr158Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T158R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNJ5
NM_000890.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 9.32

Publications

79 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000890.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-128911746-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1467663.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 11-128911745-A-G is Pathogenic according to our data. Variant chr11-128911745-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30125.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNJ5	NM_000890.5 link	c.472A>G	p.Thr158Ala	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2 link	c.472A>G	p.Thr158Ala	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.472A>G	p.Thr158Ala	missense_variant	Exon 2 of 3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNJ5	ENST00000529694.6 link	c.472A>G	p.Thr158Ala	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4 link	c.472A>G	p.Thr158Ala	missense_variant	Exon 3 of 4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1 link	c.472A>G	p.Thr158Ala	missense_variant	Exon 1 of 2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Aldosterone-producing adrenal adenoma, somatic

Pathogenic:1

Mar 25, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Familial hyperaldosteronism type III

Pathogenic:1

Mar 25, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Andersen Tawil syndrome

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.1

M;M;M

PhyloP100

9.3

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.018

D;D;D

Polyphen

0.082

B;B;B

Vest4

0.95

MutPred

0.89

Loss of ubiquitination at K160 (P = 0.0821);Loss of ubiquitination at K160 (P = 0.0821);Loss of ubiquitination at K160 (P = 0.0821);

MVP

0.95

MPC

0.50

ClinPred

0.99

GERP RS

5.5

Varity_R

0.77

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over