rs864622292

Variant names:

• chr17-70175446-CCA-TTT
• rs864622292
• NM_000891.3:c.407_409delCCAinsTTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PP2 PP3 PP5_Moderate

The NM_000891.3(KCNJ2):​c.407_409delCCAinsTTT​(p.SerIle136PhePhe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000259998: These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. PMID:11371347, 12163457, 12909315, 14522976, 22002906" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91
• Publications: 0 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 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000259998: These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. PMID: 11371347, 12163457, 12909315, 14522976, 22002906; SCV001576791: These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. PMID: 11371347, 12163457, 12909315, 14522976, 22002906
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000891.3
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-70175446-CCA-TTT is Pathogenic according to our data. Variant chr17-70175446-CCA-TTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 219878.Status of the report is criteria_provided_single_submitter, 1 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.407_409delCCAinsTTT	p.SerIle136PhePhe	missense	N/A	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.407_409delCCAinsTTT	p.SerIle136PhePhe	missense	N/A	ENSP00000243457.2	P63252
	KCNJ2	ENST00000535240.1	TSL:1	c.407_409delCCAinsTTT	p.SerIle136PhePhe	missense	N/A	ENSP00000441848.1	P63252
	KCNJ2	ENST00000854891.1		c.407_409delCCAinsTTT	p.SerIle136PhePhe	missense	N/A	ENSP00000524950.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Andersen Tawil syndrome (1)
1	-	-	Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864622292; hg19: chr17-68171587;