5-45303695-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP5BP4BS2
The NM_021072.4(HCN1):c.1522G>A(p.Val508Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,562 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508L) has been classified as Uncertain significance.
Frequency
Consequence
NM_021072.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN1 | NM_021072.4 | c.1522G>A | p.Val508Met | missense_variant | 6/8 | ENST00000303230.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN1 | ENST00000303230.6 | c.1522G>A | p.Val508Met | missense_variant | 6/8 | 1 | NM_021072.4 | P2 | |
HCN1 | ENST00000673735.1 | c.1522G>A | p.Val508Met | missense_variant | 6/9 | A2 | |||
HCN1 | ENST00000637305.1 | n.685G>A | non_coding_transcript_exon_variant | 5/7 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250768Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135500
GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461382Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 726984
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74388
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 508 of the HCN1 protein (p.Val508Met). This variant is present in population databases (rs180790607, gnomAD 0.01%). This missense change has been observed in individuals with HCN1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 530453). 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%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at