rs1554431441
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.66_67insT(p.Glu23Ter) variant causes a frameshift change involving the alteration of a non-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: 22)
Consequence
KCNH2
NM_000238.4 frameshift
NM_000238.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.13
Genes affected
KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 739 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-150977847-C-CA is Pathogenic according to our data. Variant chr7-150977847-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.66_67insT | p.Glu23Ter | frameshift_variant | 1/15 | ENST00000262186.10 | |
KCNH2 | NM_172056.3 | c.66_67insT | p.Glu23Ter | frameshift_variant | 1/9 | ||
KCNH2 | NR_176254.1 | n.474_475insT | non_coding_transcript_exon_variant | 1/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.66_67insT | p.Glu23Ter | frameshift_variant | 1/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000532957.5 | n.289_290insT | non_coding_transcript_exon_variant | 1/9 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2018 | This sequence change creates a premature translational stop signal (p.Glu23*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). This variant has not been reported in the literature in individuals with KCNH2-related disease. This variant is not present in population databases (ExAC no frequency). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at