rs786205418

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_StrongBS1_SupportingBS2

The NM_005477.3(HCN4):c.1209+2_1209+3insGAGT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

HCN4
NM_005477.3 splice_donor, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 9.20

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:

LOC105370890 (HGNC:):

LOC105370890 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11738649 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: gagGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000026 (38/1461688) while in subpopulation EAS AF= 0.000957 (38/39696). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.1209+2_1209+3insGAGT		splice_donor_variant, intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1	Q9Y3Q4
LOC105370890	NR_188273.1 link	n.590_591insTCAC		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 link	c.1209+2_1209+3insGAGT		splice_donor_variant, intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

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:

0.000386

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

AF:

0.0000260

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000957

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:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 8

Pathogenic:1Uncertain:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the HCN4 gene. It does not directly change the encoded amino acid sequence of the HCN4 protein. RNA analysis indicates that this variant induces altered splicing and may 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Brugada syndrome and/or clinical features of HCN4-related conditions (PMID: 19165230, 36381173). This variant is also known as c.1209_1209+1insGTGA or IVS2DS. ClinVar contains an entry for this variant (Variation ID: 5177). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 19165230). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. -

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ventricular tachycardia

Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype

Uncertain:1

Nov 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1209+2_1209+3insGAGT intronic variant results from an insertion of 4 nucleotides between positions c.1209+2 and c.1209+3 after coding exon 2 of the HCN4 gene. This variant (also referred to as IVS2DS and c.1209_1209+1insGTGA) has been detected in an individual with symptomatic ventricular tachycardia in whom evaluation revealed features suggestive of Brugada syndrome (Ueda K et al. J Hum Genet, 2009 Feb;54:115-21), and in an individual with bradycardia and intraventricular conduction delay (Ng D et al. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46). A minigene assay suggested this variant may result in aberrantly spliced RT-PCR product in addition to normally spliced product (Ueda K et al. J Hum Genet, 2009 Feb;54:115-21). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. 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

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