Variant 15-73322592-CAAAG-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005477.3(HCN4):c.3497_3500delCTTT(p.Ser1166fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,610,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HCN4
NM_005477.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.29

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]

HCN4 links:

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 0.0318 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.3497_3500delCTTT	p.Ser1166fs	frameshift_variant	8/8	ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 linkuse as main transcript	c.2279_2282delCTTT	p.Ser760fs	frameshift_variant	7/7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.3497_3500delCTTT	p.Ser1166fs	frameshift_variant	8/8	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000207

AC:

AN:

241526

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

131268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1458706

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

725294

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000450

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2016	The c.3497_c.3500delCTTT variant in the HCN4 gene has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. This variant causes a shift in reading frame starting at codon Serine 1166, changing it to a Cysteine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Ser1166CysfsX14. This variant is expected to result in an abnormal, truncated protein product. However, the majority of mutations in HCN4 are missense changes indicating haploinsufficiency of HCN4 may not be sufficient to cause an arrhythmia phenotype. With the information available at this time, we cannot definitively determine if c.3497_c.3500delCTTT is a disease-causing mutation or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 05, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF in last exon, and there is not enough evidence to support pathogenicity of LOF variants for this gene -

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

Dec 27, 2021

- -

Brugada syndrome 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Ser1166Cysfs*14) in the HCN4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HCN4 cause disease. This variant is present in population databases (rs774674047, gnomAD 0.006%). 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: 190785). 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

Nov 29, 2022

The c.3497_3500delCTTT variant, located in coding exon 8 of the HCN4 gene, results from a deletion of 4 nucleotides at nucleotide positions 3497 to 3500, causing a translational frameshift with a predicted alternate stop codon (p.S1166Cfs*14). This alteration occurs at the 3' terminus of theHCN4 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 38 amino acids (3%) of the protein. The exact functional effect of this alteration is unknown. In addition, 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over