rs199473385

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM5PP2PP3_ModeratePP5_ModerateBS2

The NM_000891.3(KCNJ2):c.779G>A(p.Arg260His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R260P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KCNJ2
NM_000891.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-70175818-G-C is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNJ2. . Gene score misZ 2.7459 (greater than the threshold 3.09). Trascript score misZ 3.9347 (greater than threshold 3.09). GenCC has associacion of gene with long QT syndrome, short QT syndrome, Andersen-Tawil syndrome, familial atrial fibrillation, short QT syndrome type 3, catecholaminergic polymorphic ventricular tachycardia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 17-70175818-G-A is Pathogenic according to our data. Variant chr17-70175818-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1477795.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3 linkuse as main transcript	c.779G>A	p.Arg260His	missense_variant	2/2	ENST00000243457.4	NP_000882.1	P63252

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 linkuse as main transcript	c.779G>A	p.Arg260His	missense_variant	2/2	1	NM_000891.3	ENSP00000243457.2		P63252
KCNJ2	ENST00000535240.1 linkuse as main transcript	c.779G>A	p.Arg260His	missense_variant	2/2	1		ENSP00000441848.1		P63252

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251444

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 260 of the KCNJ2 protein (p.Arg260His). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNJ2-related conditions. 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 KCNJ2 protein function. This variant disrupts the p.Arg260 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21148745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.78

.;T

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.99

D;D

Vest4

0.81

MutPred

0.76

Gain of glycosylation at S256 (P = 0.1205);Gain of glycosylation at S256 (P = 0.1205);

MVP

0.97

MPC

2.1

ClinPred

0.97

GERP RS

6.1

Varity_R

0.67

gMVP

0.91

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