17-70175446-CCA-TTT

Position:

• chr17-70175446-CCA-TTT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• 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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a disulfide_bond (size 32) in uniprot entity KCNJ2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000891.3
• 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.
• 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 id is 219878.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.407_409delCCAinsTTT	p.SerIle136PhePhe	missense_variant		ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4	c.407_409delCCAinsTTT	p.SerIle136PhePhe	missense_variant		1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1	c.407_409delCCAinsTTT	p.SerIle136PhePhe	missense_variant		1		ENSP00000441848.1

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2016

This variant, c.407_409delCCAinsTTT, is a complex sequence change that results in the deletion of 2 amino acids  (Ser and Ile) and the insertion of 2 amino acids (Phe and Phe) to the KCNJ2 protein (p.Ser136_Ile137delinsPhePhe), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases and has not been published in the literature. This sequence change introduces two phenylalanine residues at the p.136 and p.137 codons. A missense substitution which introduces one phenylalanine at this position (p.Ser136Phe) has been reported in an individual affected with Andersen-Tawil syndrome and has been shown to be deleterious by causing a dominant negative effect (PMID: 11371347, 12163457, 12909315, 14522976, 22002906). These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. In summary, this is a novel in-frame sequence change which affects an important residue required for KCNJ2 protein function. For these reasons, this variant has been classified as Likely Pathogenic. -

Andersen Tawil syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2016

This variant, c.407_409delCCAinsTTT, is a complex sequence change that results in the deletion of 2 amino acids (Ser and Ile) and the insertion of 2 amino acids (Phe and Phe) to the KCNJ2 protein (p.Ser136_Ile137delinsPhePhe), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases and has not been published in the literature. This sequence change introduces two phenylalanine residues at the p.136 and p.137 codons. A missense substitution which introduces one phenylalanine at this position (p.Ser136Phe) has been reported in an individual affected with Andersen-Tawil syndrome and has been shown to be deleterious by causing a dominant negative effect (PMID: 11371347, 12163457, 12909315, 14522976, 22002906). These results indicate that the serine residue at p.136 is required for adequate KCNJ2 protein function. In summary, this is a novel in-frame sequence change which affects an important residue required for KCNJ2 protein function. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622292; hg19: chr17-68171587;