rs7118833

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000890.5(KCNJ5):c.834T>A(p.His278Gln) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H278H) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

KCNJ5
NM_000890.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.09

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5 link	c.834T>A	p.His278Gln	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.834T>A	p.His278Gln	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.834T>A	p.His278Gln	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.834T>A	p.His278Gln	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5	ENST00000338350.4 link	c.834T>A	p.His278Gln	missense_variant	Exon 3 of 4	1		ENSP00000339960.4	P48544
KCNJ5	ENST00000533599.1 link	c.834T>A	p.His278Gln	missense_variant	Exon 1 of 2	1		ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461336

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 13;C3838758:Familial hyperaldosteronism type III

Uncertain:1

Mar 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Uncertain:1

Apr 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with early-onset hypertension (PMID: 31388123). This sequence change replaces histidine with glutamine at codon 278 of the KCNJ5 protein (p.His278Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;D;D

Eigen

Benign

0.081

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.25

LIST_S2

Pathogenic

1.0

.;.;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;H

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.5

D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.94

MutPred

0.95

Loss of catalytic residue at I276 (P = 0.1029);Loss of catalytic residue at I276 (P = 0.1029);Loss of catalytic residue at I276 (P = 0.1029);

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

-0.73

Varity_R

0.95

gMVP

0.95

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over