rs147750704

chr17-70175316-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V93A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 B:3 O:1
• Conservation: PhyloP100: 2.75

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a transmembrane_region Helical; Name=M1 (size 24) in uniprot entity KCNJ2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000891.3
• PP2: Missense variant where missense usually causes diseases, KCNJ2
• BP4: Computational evidence support a benign effect (MetaRNN=0.14038351).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ2	NM_000891.3	c.277G>A	p.Val93Ile	missense_variant	2/2	ENST00000243457.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ2	ENST00000243457.4	c.277G>A	p.Val93Ile	missense_variant	2/2	1	NM_000891.3	P1
KCNJ2	ENST00000535240.1	c.277G>A	p.Val93Ile	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152180 Hom.: 0 Cov.: 32

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: 39 AN: 251482 Hom.: 1 AF XY: 0.000169 AC XY: 23 AN XY: 135918

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.: 1 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 727248

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: 11 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74468

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.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Atrial fibrillation, familial, 9 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2017	The KCNJ2 c.277G>A (p.Val93Ile) variant has been reported one study in association with familial atrial fibrillation (AF) in which it is found in a heterozygous state in all five affected members of the same Chinese Han family; the proband, two siblings, father and niece (Xia et al. 2005). The proband had paroxysmal AF two to three times a month. His father and older sister were in permanent AF prior to death, his younger sister suffered from paroxysmal AF once or twice a week and his niece showed paroxysmal AF on a 24 hour ECG. All affected individuals were greater than 50 years of age at diagnosis. The variant was also found in a heterozygous state in two nephews, neither of whom showed paroxysmal AF on a 24 hour ECG, but who were 42 and 33 years of age at the time of study. The variant was not found in any other unaffected family members. The p.Val93Ile variant was also absent from 420 unrelated healthy Chinese individuals but is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Consortium. The p.Val931Ile variant is located in the outer helix of the M1 transmembrane domain of the protein which is a highly conserved region. Electrophysiological evaluation using whole-cell patch-clamping in COS-7 and HEK293 cells showed higher amplitude potentials compared to wildtype, demonstrating a gain of function effect of the variant on inward and outward KCNJ2 currents (Xia et al. 2005). Based on the evidence, the p.Val93Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial atrial fibrillation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, flagged submission	literature only	OMIM	Jul 15, 2005	- -
Likely pathogenic, flagged submission	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Dec 17, 2021	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. -

Atrial fibrillation Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	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. -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2020

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) -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: PM1, BP4 -

Andersen Tawil syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 19, 2017

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 19, 2017

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	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	15
Dann	Benign	0.89
DEOGEN2	Uncertain	0.58	D;D
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.86	L;L
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.65	T
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	T
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

Other links and lift over

dbSNP: rs147750704; hg19: chr17-68171457; COSMIC: COSV54660452;