rs199473384

Variant names:

• chr17-70175692-G-A
• rs199473384
• NM_000891.3:c.653G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-70175692-G-A
• chr17-70175692-G-C
• chr17-70175692-G-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000891.3(KCNJ2):​c.653G>A​(p.Arg218Gln) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005184761: Multiple publications report experimental evidence and indicate an impact on protein function (Tristani-Firouzi_2002, Seebohm_2012, Bendahhou_2003). The following publications have been ascertained in the context of this evaluation (PMID:12796536, 17221872, 11371347, 12163457, 14522976, 22002906, 17211524).; SCV000321798: Published functional studies demonstrate this variant exerts a dominant-negative effect on channel function (Bendahhou et al., 2003; Tristani-Firouzi et al., 2002); SCV000260176: Experimental studies have shown that this missense change affects KCNJ2 function (PMID:11371347, 12086641, 14522976, 16834334, 22002906).; SCV002658971: "In vitro functional assays have indicated this variant to result in reduced channel current, and dominant negative effect." PMID:12208847 PMID:14578380". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 10.0
• Publications: 38 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• short QT syndrome type 3

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

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

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005184761: Multiple publications report experimental evidence and indicate an impact on protein function (Tristani-Firouzi_2002, Seebohm_2012, Bendahhou_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12796536, 17221872, 11371347, 12163457, 14522976, 22002906, 17211524).; SCV000321798: Published functional studies demonstrate this variant exerts a dominant-negative effect on channel function (Bendahhou et al., 2003; Tristani-Firouzi et al., 2002); SCV000260176: Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 11371347, 12086641, 14522976, 16834334, 22002906).; SCV002658971: "In vitro functional assays have indicated this variant to result in reduced channel current, and dominant negative effect." PMID:12208847 PMID:14578380
• 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 chr17-70175692-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190813.
• 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, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, congenital heart disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-70175692-G-A is Pathogenic according to our data. Variant chr17-70175692-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 67585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000891.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ2	NM_000891.3	MANE Select	c.653G>A	p.Arg218Gln	missense	Exon 2 of 2	NP_000882.1	P63252

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ2	ENST00000243457.4	TSL:1 MANE Select	c.653G>A	p.Arg218Gln	missense	Exon 2 of 2	ENSP00000243457.2	P63252
	KCNJ2	ENST00000535240.1	TSL:1	c.653G>A	p.Arg218Gln	missense	Exon 2 of 2	ENSP00000441848.1	P63252
	KCNJ2	ENST00000854891.1		c.653G>A	p.Arg218Gln	missense	Exon 3 of 3	ENSP00000524950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Andersen Tawil syndrome (5)
1	-	-	Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 (1)
1	-	-	Andersen Tawil syndrome;C1865018:Short QT syndrome type 3;C3151431:Atrial fibrillation, familial, 9 (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	not provided (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Loss of MoRF binding (P = 0.0382)
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.99
Mutation Taster		=7/93	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: rs199473384; hg19: chr17-68171833; COSMIC: COSV54662748;