rs538668505
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005477.3(HCN4):c.2995C>T(p.Arg999Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000635 in 1,590,086 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R999Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.2995C>T | p.Arg999Trp | missense_variant | 8/8 | ENST00000261917.4 | |
HCN4 | XM_011521148.3 | c.1777C>T | p.Arg593Trp | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.2995C>T | p.Arg999Trp | missense_variant | 8/8 | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152124Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000240 AC: 5AN: 208582Hom.: 0 AF XY: 0.0000173 AC XY: 2AN XY: 115760
GnomAD4 exome AF: 0.0000647 AC: 93AN: 1437844Hom.: 0 Cov.: 34 AF XY: 0.0000715 AC XY: 51AN XY: 713278
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74450
ClinVar
Submissions by phenotype
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 04, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 575202; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 999 of the HCN4 protein (p.Arg999Trp). 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 variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 575202). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN4 protein function with a negative predictive value of 95%. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2023 | The p.R999W variant (also known as c.2995C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2995. The arginine at codon 999 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at