chr5-45695966-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_021072.4(HCN1):c.128C>A(p.Pro43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000604 in 1,324,782 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P43L) has been classified as Likely benign.
Frequency
Consequence
NM_021072.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN1 | NM_021072.4 | c.128C>A | p.Pro43Gln | missense_variant | 1/8 | ENST00000303230.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN1 | ENST00000303230.6 | c.128C>A | p.Pro43Gln | missense_variant | 1/8 | 1 | NM_021072.4 | P2 | |
HCN1 | ENST00000673735.1 | c.128C>A | p.Pro43Gln | missense_variant | 1/9 | A2 | |||
HCN1 | ENST00000634658.1 | c.128C>A | p.Pro43Gln | missense_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000134 AC: 2AN: 149496Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000511 AC: 6AN: 1175170Hom.: 0 Cov.: 32 AF XY: 0.00000523 AC XY: 3AN XY: 573228
GnomAD4 genome AF: 0.0000134 AC: 2AN: 149612Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1AN XY: 73020
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 43 of the HCN1 protein (p.Pro43Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HCN1-related conditions. 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 HCN1 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