15-73322587-CCAAA-C

Position:

• chr15-73322587-CCAAA-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: HCN4 ENST00000261917.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 5.59

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]

ACMG classification

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
HCN4	NM_005477.3	c.3502_3505del	p.Phe1168GlyfsTer12	frameshift_variant	8/8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.2284_2287del	p.Phe762GlyfsTer12	frameshift_variant	7/7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.3502_3505del	p.Phe1168GlyfsTer12	frameshift_variant	8/8	1	NM_005477.3	ENSP00000261917	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152144 Hom.: 0 Cov.: 33

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

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

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

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

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	Reported 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 provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Sinoatrial node disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Brugada syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This 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 submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The 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

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

Other links and lift over

dbSNP: rs786205259; hg19: chr15-73614928;