rs199473381

Variant names:

• chr17-70175605-G-A
• rs199473381
• NM_000891.3:c.566G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-70175605-G-A
• chr17-70175605-G-C
• chr17-70175605-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000891.3(KCNJ2):​c.566G>A​(p.Arg189Lys) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Andersen-Tawil syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• short QT syndrome type 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• long QT syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000891.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-70175604-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 429589.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 short QT syndrome type 3, short QT syndrome, Andersen-Tawil syndrome, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 17-70175605-G-A is Pathogenic according to our data. Variant chr17-70175605-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190812.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.566G>A	p.Arg189Lys	missense_variant	Exon 2 of 2	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4	c.566G>A	p.Arg189Lys	missense_variant	Exon 2 of 2	1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1	c.566G>A	p.Arg189Lys	missense_variant	Exon 2 of 2	1		ENSP00000441848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Arg189 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ2-related conditions (PMID: 12796536, 27145478), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 190812). This missense change has been observed in individual(s) with Anderson-Tawil sydnrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 189 of the KCNJ2 protein (p.Arg189Lys). -

not provided Pathogenic:1

Mar 21, 2013

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg189Lys (AGA>AAA): c.566 G>A in exon 2 of the KCNJ2 gene (NM_000891.2). The Arg189Lys variant in the KCNJ2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg189Lys results in a conservative amino acid substitution of one positively charged amino acid with another, it occurs at a position that is conserved across species. In silico analysis predicts Arg189Lys is probably damaging to the protein structure/function. Mutations at this codon (Arg189Ile) and in nearby residues (Pro186Leu, Thr192Ala, Thr192Ile) have been reported in association with ATS, further supporting the functional importance of this codon and this region of the protein. Furthermore, the Arg189Lys variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Arg189Lys is a good candidate for a disease-causing mutation, with the information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.86		Gain of methylation at R189 (P = 0.0293);Gain of methylation at R189 (P = 0.0293);
MVP		0.99
MPC		2.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.99
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473381; hg19: chr17-68171746;