chr17-70176084-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_000891.3(KCNJ2):​c.1045G>A​(p.Glu349Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

KCNJ2
NM_000891.3 missense

Scores

8
7
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

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, 0.8
BS2
High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNJ2NM_000891.3 linkuse as main transcriptc.1045G>A p.Glu349Lys missense_variant 2/2 ENST00000243457.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNJ2ENST00000243457.4 linkuse as main transcriptc.1045G>A p.Glu349Lys missense_variant 2/21 NM_000891.3 P1
KCNJ2ENST00000535240.1 linkuse as main transcriptc.1045G>A p.Glu349Lys missense_variant 2/21 P1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251262
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
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:
0.0000130
AC:
19
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.000507
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.000178
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3;C3151431:Atrial fibrillation, familial, 9 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 26, 2022- -
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 14, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 349 of the KCNJ2 protein (p.Glu349Lys). This variant is present in population databases (rs375330016, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with KCNJ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 190818). 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. 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 submitterclinical testingGeneDxMar 07, 2024Identified in a case of Sudden Infant Death Syndrome (SIDS) in published literature (PMID: 32145446); A published functional study suggests the p.(E349K) variant results in no change of inward rectification compared to wildtype (PMID: 12407079); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12407079, 32145446) -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 24, 2023This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Uncertain
2.3
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-3.3
D;D
REVEL
Pathogenic
0.75
Sift
Benign
0.084
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.98
D;D
Vest4
0.79
MVP
0.84
MPC
2.0
ClinPred
0.78
D
GERP RS
5.8
Varity_R
0.66
gMVP
0.73

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.

Other links and lift over

dbSNP: rs375330016; hg19: chr17-68172225; COSMIC: COSV54662217; API