rs1165134160
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005477.3(HCN4):āc.3353T>Cā(p.Leu1118Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,562,866 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 (ā ).
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.3353T>C | p.Leu1118Pro | missense_variant | 8/8 | ENST00000261917.4 | NP_005468.1 | |
HCN4 | XM_011521148.3 | c.2135T>C | p.Leu712Pro | missense_variant | 7/7 | XP_011519450.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.3353T>C | p.Leu1118Pro | missense_variant | 8/8 | 1 | NM_005477.3 | ENSP00000261917.3 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000440 AC: 7AN: 158930Hom.: 0 AF XY: 0.0000350 AC XY: 3AN XY: 85776
GnomAD4 exome AF: 0.00000496 AC: 7AN: 1410648Hom.: 0 Cov.: 36 AF XY: 0.00000430 AC XY: 3AN XY: 696872
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74368
ClinVar
Submissions by phenotype
Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with HCN4-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces leucine with proline at codon 1118 of the HCN4 protein (p.Leu1118Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at