chr7-150947428-G-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_000238.4(KCNH2):āc.3052C>Gā(p.Pro1018Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,556,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.3052C>G | p.Pro1018Ala | missense_variant | 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.3052C>G | p.Pro1018Ala | missense_variant | Exon 13 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.2032C>G | p.Pro678Ala | missense_variant | Exon 9 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3885C>G | non_coding_transcript_exon_variant | Exon 11 of 13 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000256 AC: 4AN: 156200Hom.: 0 AF XY: 0.0000355 AC XY: 3AN XY: 84544
GnomAD4 exome AF: 0.0000399 AC: 56AN: 1404134Hom.: 0 Cov.: 36 AF XY: 0.0000375 AC XY: 26AN XY: 693004
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74456
ClinVar
Submissions by phenotype
not provided Uncertain:2
The KCNH2 c.3052C>G; p.Pro1018Ala variant (rs41313764) is reported in the literature in an individual affected with atrial fibrillation, though it was not demonstrated to be disease-causing (Donate Puertas 2018). This variant is found on only four chromosomes (4/156200 alleles) in the Genome Aggregation Database. The proline at codon 1018 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro1018Ala variant is uncertain at this time. References: Donate Puertas R et al. Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation. Biomed Res Int. 2018;2018:4862480. -
Reported in individuals with various cardiac disorders, including dilated cardiomyopathy, ventricular tachycardia, paroxysmal atrial fibrillation, and unspecified arrhythmia (Doate Puertas et al., 2018; Herkert et al., 2018; van Lint et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29517769, 30847666, 30276209) -
Long QT syndrome Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1018 of the KCNH2 protein (p.Pro1018Ala). This variant is present in population databases (rs41313764, gnomAD 0.005%). This missense change has been observed in individual(s) with atrial fibrillation, unknown arrhythmia, left ventricular noncompaction and dilated cardiomyopathy (PMID: 28798025, 29517769, 30276209, 30847666). ClinVar contains an entry for this variant (Variation ID: 200520). 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 disruptive. 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 proline with alanine at codon 1018 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 reported for this variant. This variant has been reported in individuals affected with arrhythmias (PMID: 30276209, 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 28798025). This variant has been identified in 4/156200 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. -
Cardiac arrhythmia Uncertain:1
This missense variant replaces proline with alanine at codon 1018 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 reported for this variant. This variant has been reported in individuals affected with arrhythmias (PMID: 30276209, 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 28798025). This variant has been identified in 4/156200 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at