15-73322788-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_005477.3(HCN4):c.3305G>A(p.Arg1102His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,552,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000381 AC: 6AN: 157608Hom.: 0 AF XY: 0.0000591 AC XY: 5AN XY: 84660
GnomAD4 exome AF: 0.0000293 AC: 41AN: 1400072Hom.: 0 Cov.: 36 AF XY: 0.0000275 AC XY: 19AN XY: 689948
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74458
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 29, 2023 | 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. 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1102 of the HCN4 protein (p.Arg1102His). 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 clinical features of HCN4-related conditions (PMID: 32508047). ClinVar contains an entry for this variant (Variation ID: 579697). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 02, 2024 | The p.R1102H variant (also known as c.3305G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3305. The arginine at codon 1102 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals with sudden death and cardiac dysrhythmia; however, clinical details were limited and/or other variants in cardiac related genes were also detected (Campuzano O et al. Forensic Sci. Int. 2017 Feb;271:120-125). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at