15-73322800-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005477.3(HCN4):c.3293C>T(p.Ala1098Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,541,130 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A1098A) has been classified as Likely benign.
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.3293C>T | p.Ala1098Val | missense_variant | 8/8 | ENST00000261917.4 | |
HCN4 | XM_011521148.3 | c.2075C>T | p.Ala692Val | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.3293C>T | p.Ala1098Val | missense_variant | 8/8 | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000195 AC: 3AN: 153722Hom.: 0 AF XY: 0.0000368 AC XY: 3AN XY: 81614
GnomAD4 exome AF: 0.0000230 AC: 32AN: 1388820Hom.: 0 Cov.: 36 AF XY: 0.0000293 AC XY: 20AN XY: 682362
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #425072; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2016 | - - |
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 11, 2021 | - - |
Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1098 of the HCN4 protein (p.Ala1098Val). 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 dilated cardiomyopathy (PMID: 28254189). ClinVar contains an entry for this variant (Variation ID: 425072). 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 | Feb 16, 2023 | The p.A1098V variant (also known as c.3293C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 3293. The alanine at codon 1098 is replaced by valine, an amino acid with similar properties. This variant was reported in an individual with dilated cardiomyopathy with limited clinical details provided (Arbustini E et al. J. Am. Coll. Cardiol., 2017 Mar;69:1210-1211). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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