chr15-73323556-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_005477.3(HCN4):c.2537C>T(p.Pro846Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000487 in 1,600,826 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000106 AC: 25AN: 235816Hom.: 0 AF XY: 0.000117 AC XY: 15AN XY: 128586
GnomAD4 exome AF: 0.0000490 AC: 71AN: 1448640Hom.: 0 Cov.: 35 AF XY: 0.0000638 AC XY: 46AN XY: 721114
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Cardiovascular phenotype Uncertain:1
The p.P846L variant (also known as c.2537C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2537. The proline at codon 846 is replaced by leucine, an amino acid with similar properties. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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. -
Brugada syndrome 8 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at