rs147750704

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBS1_SupportingBS2

The NM_000891.3(KCNJ2):c.277G>A(p.Val93Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KCNJ2
NM_000891.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:4O:1

Conservation

PhyloP100: 2.75

Variant links:

Genes affected

KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

KCNJ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a transmembrane_region Helical; Name=M1 (size 24) in uniprot entity KCNJ2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000891.3

PP2

Missense variant in the KCNJ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.7459 (below the threshold of 3.09). Trascript score misZ: 3.9347 (above the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome, short QT syndrome, Andersen-Tawil syndrome, familial atrial fibrillation, short QT syndrome type 3, catecholaminergic polymorphic ventricular tachycardia.

BP4

Computational evidence support a benign effect (MetaRNN=0.14038351).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000118 (172/1461894) while in subpopulation SAS AF= 0.000336 (29/86258). AF 95% confidence interval is 0.00024. There are 1 homozygotes in gnomad4_exome. There are 93 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ2	NM_000891.3 link	c.277G>A	p.Val93Ile	missense_variant	Exon 2 of 2	ENST00000243457.4	NP_000882.1	P63252

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 link	c.277G>A	p.Val93Ile	missense_variant	Exon 2 of 2	1	NM_000891.3	ENSP00000243457.2		P63252
KCNJ2	ENST00000535240.1 link	c.277G>A	p.Val93Ile	missense_variant	Exon 2 of 2	1		ENSP00000441848.1		P63252

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251482

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 9

Pathogenic:2

Dec 17, 2021

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We observed p.V93I variant in a 15-y.o. female proband with borderline QTc prolongation. This variant was shown to have in vitro effect (PS3 criteria); several in silico tools predict the variant to be pathogenic (PP3 criteria); additionally, it was previously shown for the variant to have a gain-of-function effect of this variant on Kir2.1 channel. Based on the evidence, we consider the p.V93I variant to be likely pathogenic. -

Jul 15, 2005

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

not provided

Uncertain:1Benign:1

Jan 16, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 23631430, 15922306, 19041665, 29247119, 25410959) -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNJ2: BS1 -

Atrial fibrillation

Uncertain:1Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:15922306;PMID:19041665). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Uncertain:1

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 93 of the KCNJ2 protein (p.Val93Ile). This variant is present in population databases (rs147750704, gnomAD 0.03%). This missense change has been observed in individual(s) with atrial fibrillation and/or long QT syndrome (PMID: 15922306, 23631430, 25410959, 35456365). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30121). 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 not expected to disrupt KCNJ2 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNJ2 function (PMID: 15922306, 19041665, 19111761). 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. -

Long QT syndrome

Uncertain:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PM1, BP4 -

Andersen Tawil syndrome

Benign:1

Sep 19, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Jun 30, 2022

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. -

Short QT syndrome type 3

Benign:1

Sep 19, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.00033

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.58

D;D

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.86

L;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.070

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.38

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0040

B;B

Vest4

0.051

MVP

0.97

MPC

0.68

ClinPred

0.025

GERP RS

3.5

Varity_R

0.020

gMVP

0.74

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