GeneBe

rs1277827477

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_005477.3(HCN4):​c.2783delC​(p.Pro928ArgfsTer57) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HCN4
NM_005477.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52
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_pathogenic. Variant got 6 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 0.23 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCN4NM_005477.3 linkc.2783delC p.Pro928ArgfsTer57 frameshift_variant Exon 8 of 8 ENST00000261917.4 NP_005468.1 Q9Y3Q4
HCN4XM_011521148.3 linkc.1565delC p.Pro522ArgfsTer57 frameshift_variant Exon 7 of 7 XP_011519450.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HCN4ENST00000261917.4 linkc.2783delC p.Pro928ArgfsTer57 frameshift_variant Exon 8 of 8 1 NM_005477.3 ENSP00000261917.3 Q9Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151800
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1395940
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
686516
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151800
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74140
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Oct 05, 2016
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2783delC variant, located in coding exon 8 of the HCN4 gene, results from a deletion of one nucleotide at nucleotide position 2783, causing a translational frameshift with a predicted alternate stop codon (p.P928Rfs*57). This frameshift occurs in the 3' terminal exon of HCN4, and is not expected to trigger nonsense-mediated mRNA decay. Rather, this deletion results in truncation and loss of the C-terminal 277 amino acids of the HCN4 channel. The exact functional impact of the loss of these amino acids is unknown at this time. Frameshift variants are typically deleterious in nature. However, loss of function through HCN4 protein truncation has not been clearly established as a mechanism of disease. Prior studies reporting HCN4 frameshift and splice alterations did not demonstrate that channel truncation was truly pathogenic in the patients in whom the sequence alterations were identified (Ueda K et al. J Hum Genet. 2009;54(2):115-21; Schweizer PA et al. Circ Arrhythm Electrophysiol. 2010;3(5):542-52; Verkerk AO et al. Europace. 2014;16(3):384-95). In addition, this variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5877 samples (11754 alleles) with coverage at this position. 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: rs1277827477; hg19: chr15-73615650; API