rs779241036
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_005477.3(HCN4):c.2555C>T(p.Pro852Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,600,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P852P) has been classified as Benign.
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000849 AC: 2AN: 235594Hom.: 0 AF XY: 0.0000156 AC XY: 2AN XY: 128498
GnomAD4 exome AF: 0.00000759 AC: 11AN: 1448704Hom.: 0 Cov.: 35 AF XY: 0.00000832 AC XY: 6AN XY: 721100
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1
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not provided Uncertain:1
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Brugada syndrome 8 Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 852 of the HCN4 protein (p.Pro852Leu). This variant is present in population databases (rs779241036, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and atrioventricular block (PMID: 28254188). ClinVar contains an entry for this variant (Variation ID: 289273). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at