rs1060500054

Positions:

• chr17-70176130-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000891.3(KCNJ2):​c.1091A>G​(p.Lys364Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.29

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2928445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.1091A>G	p.Lys364Arg	missense_variant	2/2	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4	c.1091A>G	p.Lys364Arg	missense_variant	2/2	1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1	c.1091A>G	p.Lys364Arg	missense_variant	2/2	1		ENSP00000441848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNJ2-related disease. This sequence change replaces lysine with arginine at codon 364 of the KCNJ2 protein (p.Lys364Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 17, 2017

p.Lys364Arg (c.1091A>G) in the KCNJ2 gene (NM_000891.2) Given lack of case data and inconsistent gene-phenotype information, yet absence in control populations, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in any published cases of long QT syndrome (not including this patient's family). There are no entries in ClinVar for this variant. It appears to be novel. Variants in the KCNJ2 gene have been associated with long QT syndrome type 7, also known as Andersen syndrome. This is a syndromic condition characterized by ventricular arrhythmias, periodic paralysis, and distinct skeletal and facial dysmorphisms. Kidney and valvular heart problems have also been reported. It is inherited in an autosomal dominant manner. Given that our patient does not have any other clinical findings, it is unlikely that this variant is contributing to her prolonged QT interval. In silico analysis with PolyPhen-2 and SIFT predicts the variant to be tolerated. The Lysine at codon 364 is highly conserved across species. No other variants have been reported in association with disease at this codon or nearby codons. There is no variation at codon listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 90x. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D
Eigen	Benign	0.052
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.039	D
MutationAssessor	Benign	0.76	N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.25
Sift	Benign	0.42	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0010	B;B
Vest4		0.53
MutPred		0.29		Loss of ubiquitination at K364 (P = 0.0081);Loss of ubiquitination at K364 (P = 0.0081);
MVP		0.69
MPC		0.74
ClinPred		0.63	D
GERP RS		6.1
Varity_R		0.22
gMVP		0.50

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: rs1060500054; hg19: chr17-68172271; COSMIC: COSV54663967;