rs786205418

Positions:

• chr15-73343382-T-TACTC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005477.3(HCN4):​c.1209+2_1209+3insGAGT variant causes a splice region, 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_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 9.20

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 -3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS2: High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.1209+2_1209+3insGAGT		splice_region_variant, intron_variant		ENST00000261917.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.1209+2_1209+3insGAGT		splice_region_variant, intron_variant		1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 33

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: 38 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727146

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: 2 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74318

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: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 8 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 23, 2023	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 (PMID: 19165230). 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. -

Ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205418; hg19: chr15-73635723;