rs560874115
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005477.3(HCN4):āc.458A>Gā(p.Glu153Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,237,616 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.458A>G | p.Glu153Gly | missense_variant | 1/8 | ENST00000261917.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.458A>G | p.Glu153Gly | missense_variant | 1/8 | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00141 AC: 212AN: 150518Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00206 AC: 3AN: 1454Hom.: 0 AF XY: 0.00350 AC XY: 3AN XY: 858
GnomAD4 exome AF: 0.00300 AC: 3262AN: 1086990Hom.: 7 Cov.: 31 AF XY: 0.00300 AC XY: 1555AN XY: 518372
GnomAD4 genome ? AF: 0.00141 AC: 212AN: 150626Hom.: 0 Cov.: 33 AF XY: 0.00135 AC XY: 99AN XY: 73602
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:7
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 13, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2021 | This variant is associated with the following publications: (PMID: 29588962, 28341588, 30847666) - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | HCN4: PP3, BS1, BS2 - |
Sick sinus syndrome 2, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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 | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | HCN4 NM_005477.2 exon 1 p.Glu153Gly (c.458A>G): This variant has been reported in the literature in one individual with genearlized epilepsy and in one individual with unspecified cardiac arrhythmia (Becker 2017 PMID:29588962, Proost 2017 PMID:28341588). This variant did not segregate with disease in at least four affected family members with epilepsy (Becker 2017 PMID:29588962). This variant is present in 0.1% (31/14734) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-73660154-T-C). This variant is present in ClinVar (Variation ID:180370). This variant amino acid Glycine (Gly) is present in several bird and fish species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. However, an in vitro functional study using voltage clamp anaylsis does predict that this variant will impact the protein by causing a hyperpolarizing shift in activation and reduced current amplitudes (Becker 2017 PMID:29588962). However, this study may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Brugada syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 28, 2014 | - - |
Primary dilated cardiomyopathy;C0878544:Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jun 11, 2019 | - - |
HCN4-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 28, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Brugada syndrome 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 22, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at