rs794728504
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.3017del(p.Gly1006AlafsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1006G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000238.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.3017del | p.Gly1006AlafsTer51 | frameshift_variant | 13/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.3017del | p.Gly1006AlafsTer51 | frameshift_variant | 13/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1997del | p.Gly666AlafsTer51 | frameshift_variant | 9/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3850del | non_coding_transcript_exon_variant | 11/13 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 7.05e-7 AC: 1AN: 1418556Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 701434
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Aug 21, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2022 | Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15840476, 15851119, 12877697, 31361068) - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2021 | For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with KCNH2-related conditions (PMID: 12877697, 15840476). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Gly1006Alafs*51) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). - |
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | KCNH2 NM_000238.3 exon 13 p.Gly1006Alafs*51 (c.3017delG): This variant has been reported in the literature in at least 3 individuals with LQTS (Nemec 2003 PMID:12877697 ). This variant is not present in large control databases but is present in ClinVar (Variation ID:200799). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 51 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Hedley 2009 PMID:19862833). In summary, this variant is classified as pathogenic based on the data above. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at