7-150947477-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.3003G>A(p.Trp1001*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000238.4 stop_gained
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.3003G>A | p.Trp1001* | stop_gained | Exon 13 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.3003G>A | p.Trp1001* | stop_gained | Exon 13 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1983G>A | p.Trp661* | stop_gained | Exon 9 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3836G>A | non_coding_transcript_exon_variant | Exon 11 of 13 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1427632Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 706916
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 2 Pathogenic:1
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not provided Pathogenic:1
Has been reported in individuals with LQTS (PMID: 11854117, 23995044); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest the p.(W1001*) variant results in a truncated protein and significant reduction in channel current properties (PMID: 12021266); Nonsense 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: 11686910, 11854117, 23995044, 17576861, 12021266) -
Long QT syndrome Pathogenic:1
This sequence change creates a premature translational stop signal at codon 1001 (p.Trp1001*) of 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. There are two different nucleotide changes (c.3002G>A and c.3003G>A) that result in the same amino acid change to a stop codon. The variant c.3002G>A has been classified as pathogenic (Invitae database). This protein change has been reported in the literature in individuals affected with long QT syndrome (PMID: 12021266, 26846766, 11854117). Experimental studies have shown that this nonsense change (p.Tryp1001*) results in reduced mRNA levels due to nonsense-mediated decay and the resulting protein is truncated, which results in a channel with reduced current amplitude (PMID: 17576861, 12021266). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at