rs199473440
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000238.4(KCNH2):c.2764C>T(p.Arg922Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,530,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R922Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2764C>T | p.Arg922Trp | missense_variant | 12/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2764C>T | p.Arg922Trp | missense_variant | 12/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1744C>T | p.Arg582Trp | missense_variant | 8/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3597C>T | non_coding_transcript_exon_variant | 10/13 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000237 AC: 3AN: 126824Hom.: 0 AF XY: 0.0000289 AC XY: 2AN XY: 69304
GnomAD4 exome AF: 0.0000116 AC: 16AN: 1378148Hom.: 0 Cov.: 36 AF XY: 0.0000162 AC XY: 11AN XY: 679342
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74280
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 07, 2023 | This missense variant replaces arginine with tryptophan at codon 922 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Electrophysiological functional studies suggest that the variant may not impact KCNH2 function (PMID: 16432067); the clinical relevance of this observation is unknown. This variant has been reported in individuals with suspected long QT syndrome (PMID: 10973849, 15051636, 19841299); one of these individuals also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID: 19841299). This variant has been identified in 3/126824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 922 of the KCNH2 protein (p.Arg922Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with prolonged QT interval (PMID: 10973849). ClinVar contains an entry for this variant (Variation ID: 67435). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 16432067, 23303164). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 21, 2023 | This missense variant replaces arginine with tryptophan at codon 922 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Electrophysiological functional studies suggest that the variant may not impact KCNH2 function (PMID: 16432067); the clinical relevance of this observation is unknown. This variant has been reported in individuals with suspected long QT syndrome (PMID: 10973849, 15051636, 19841299); one of these individuals also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID: 19841299). This variant has been identified in 3/126824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:15051636;PMID:16432067). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at