rs786205259

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The ENST00000261917.4(HCN4):​c.3502_3505del​(p.Phe1168GlyfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.000112 in 1,610,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β˜…β˜…).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

HCN4
ENST00000261917.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.59
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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 0.0305 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS2
High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HCN4NM_005477.3 linkuse as main transcriptc.3502_3505del p.Phe1168GlyfsTer12 frameshift_variant 8/8 ENST00000261917.4 NP_005468.1
HCN4XM_011521148.3 linkuse as main transcriptc.2284_2287del p.Phe762GlyfsTer12 frameshift_variant 7/7 XP_011519450.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HCN4ENST00000261917.4 linkuse as main transcriptc.3502_3505del p.Phe1168GlyfsTer12 frameshift_variant 8/81 NM_005477.3 ENSP00000261917 P1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152144
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000108
AC:
26
AN:
240632
Hom.:
0
AF XY:
0.0000841
AC XY:
11
AN XY:
130768
show subpopulations
Gnomad AFR exome
AF:
0.000132
Gnomad AMR exome
AF:
0.000147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000166
Gnomad SAS exome
AF:
0.0000674
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000121
Gnomad OTH exome
AF:
0.000170
GnomAD4 exome
AF:
0.000104
AC:
152
AN:
1458350
Hom.:
0
AF XY:
0.0000883
AC XY:
64
AN XY:
725078
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000225
Gnomad4 ASJ exome
AF:
0.0000767
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000104
Gnomad4 OTH exome
AF:
0.000183
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152144
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000155

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:5
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 31, 2023Reported in an individual in the ClinSeq Project who had a normal ECG and echocardiogram and no family history of arrhythmia or sudden cardiac death; denoted as c.3498_3501del due to alternate nomenclature (Ng et al., 2013); Has been reported as a variant of uncertain significance in an individual with Brugada syndrome (Sarquella-Brugada et al., 2021); Frameshift variant predicted to result in protein truncation as the last 36 amino acids are replaced with 11 different amino acids; This variant is associated with the following publications: (PMID: 26046366, 26582918, 23861362, 34546463) -
Uncertain significance, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Sinoatrial node disorder Uncertain:1
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthApr 05, 2018- -
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 04, 2022- -
Brugada syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This sequence change creates a premature translational stop signal (p.Phe1168Glyfs*12) in the HCN4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the HCN4 protein. This variant is present in population databases (rs771725926, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with sinus node disease (PMID: 23861362). ClinVar contains an entry for this variant (Variation ID: 191377). 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. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 27, 2023The c.3502_3505delTTTG variant, located in coding exon 8 of the HCN4 gene, results from a deletion of 4 nucleotides at nucleotide positions 3502 to 3505, causing a translational frameshift with a predicted alternate stop codon (p.F1168Gfs*12). This alteration has been reported as a secondary cardiac variant in an exome cohort, and has been detected in individuals reported to have Brugada syndrome and atrial fibrillation; however, clinical details were limited and additional variants in arrhythmia-associated genes were detected in some cases (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Sarquella-Brugada G et al. Hum Genet, 2022 Oct;141(10):1579-1589). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of HCN4 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786205259; hg19: chr15-73614928; API