rs762950777
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2
The NM_005477.3(HCN4):c.3064C>T(p.Arg1022Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,494,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
HCN4
NM_005477.3 stop_gained
NM_005477.3 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 2.94
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 Uncertain_significance. Variant got 0 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.152 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS2
?
High AC in GnomAdExome4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.3064C>T | p.Arg1022Ter | stop_gained | 8/8 | ENST00000261917.4 | |
HCN4 | XM_011521148.3 | c.1846C>T | p.Arg616Ter | stop_gained | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.3064C>T | p.Arg1022Ter | stop_gained | 8/8 | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000255 AC: 3AN: 117680Hom.: 0 AF XY: 0.0000157 AC XY: 1AN XY: 63874
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GnomAD4 exome AF: 0.0000112 AC: 15AN: 1342082Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 9AN XY: 656630
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74250
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 07, 2022 | - - |
Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | This sequence change creates a premature translational stop signal (p.Arg1022*) in the HCN4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the HCN4 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470663). 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. - |
HCN4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 03, 2023 | The HCN4 c.3064C>T variant is predicted to result in premature protein termination (p.Arg1022*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-73615370-G-A). Loss of function has not been conclusively established as a mechanism for HCN4-related disorders. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at