rs773441535
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_021072.4(HCN1):āc.280A>Gā(p.Met94Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,609,162 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 (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M94I) 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.280A>G | p.Met94Val | missense_variant | 1/8 | ENST00000303230.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN1 | ENST00000303230.6 | c.280A>G | p.Met94Val | missense_variant | 1/8 | 1 | NM_021072.4 | P2 | |
HCN1 | ENST00000673735.1 | c.280A>G | p.Met94Val | missense_variant | 1/9 | A2 | |||
HCN1 | ENST00000634658.1 | c.280A>G | p.Met94Val | missense_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000330 AC: 5AN: 151718Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000165 AC: 4AN: 242740Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 132982
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1457444Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 725230
GnomAD4 genome AF: 0.0000330 AC: 5AN: 151718Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74080
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the HCN1 protein (p.Met94Val). This variant is present in population databases (rs773441535, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of HCN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 578939). 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 80%. 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