rs786205418
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_005477.3(HCN4):c.1209+2_1209+3insGAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
HCN4
NM_005477.3 splice_region, intron
NM_005477.3 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.20
Genes affected
HCN4 (HGNC:16882): (hyperpolarization activated cyclic nucleotide gated potassium channel 4) This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
BS2
?
High AC in GnomAdExome4 at 38 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.1209+2_1209+3insGAGT | splice_region_variant, intron_variant | ENST00000261917.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.1209+2_1209+3insGAGT | splice_region_variant, intron_variant | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727146
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brugada syndrome 8 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change falls in intron 2 of the HCN4 gene. It does not directly change the encoded amino acid sequence of the HCN4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HCN4 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Brugada syndrome (PMID: 19165230). This variant is also known as c.1209_1209+1insGTGA or IVS2DS. ClinVar contains an entry for this variant (Variation ID: 5177). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 19165230). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. - |
Ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2023 | The c.1209+2_1209+3insGAGT intronic variant results from an insertion of 4 nucleotides between positions c.1209+2 and c.1209+3 after coding exon 2 of the HCN4 gene. This variant (also referred to as IVS2DS and c.1209_1209+1insGTGA) has been detected in an individual with symptomatic ventricular tachycardia in whom evaluation revealed features suggestive of Brugada syndrome (Ueda K et al. J Hum Genet, 2009 Feb;54:115-21), and in an individual with bradycardia and intraventricular conduction delay (Ng D et al. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46). A minigene assay suggested this variant may result in aberrantly spliced RT-PCR product in addition to normally spliced product (Ueda K et al. J Hum Genet, 2009 Feb;54:115-21). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at