NM_000238.4:c.2842C>T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000238.4(KCNH2):c.2842C>T(p.Arg948Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,565,084 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 (★★).
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2842C>T | p.Arg948Cys | missense_variant | Exon 12 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2842C>T | p.Arg948Cys | missense_variant | Exon 12 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1822C>T | p.Arg608Cys | missense_variant | Exon 8 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3675C>T | non_coding_transcript_exon_variant | Exon 10 of 13 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000602 AC: 10AN: 166182Hom.: 0 AF XY: 0.0000768 AC XY: 7AN XY: 91106
GnomAD4 exome AF: 0.0000354 AC: 50AN: 1412928Hom.: 0 Cov.: 36 AF XY: 0.0000415 AC XY: 29AN XY: 699314
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 948 of the KCNH2 protein (p.Arg948Cys). This variant is present in population databases (rs121912514, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16922724). ClinVar contains an entry for this variant (Variation ID: 14441). 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. 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. -
This missense variant replaces arginine with cysteine at codon 948 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 16922724, 31521807). This variant has been identified in 10/166182 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. -
Long QT syndrome 1/2, digenic Pathogenic:1
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not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with dilated cardiomyopathy and arrhythmia (Li et al., 2020); This variant is associated with the following publications: (PMID: 16922724, 31589614, 30609406, 31521807) -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
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Cardiac arrhythmia Uncertain:1
This missense variant replaces arginine with cysteine at codon 948 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 16922724, 31521807). This variant has been identified in 10/166182 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
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). 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