15-73361144-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005477.3(HCN4):c.785+6342T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,056 control chromosomes in the GnomAD database, including 10,602 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (10602 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.785+6342T>C		intron_variant		ENST00000261917.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.785+6342T>C		intron_variant		1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51356 AN: 151938 Hom.: 10558 Cov.: 33

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.314

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51460 AN: 152056 Hom.: 10602 Cov.: 33 AF XY: 0.337 AC XY: 25078 AN XY: 74324

Gnomad4 AFR AF: 0.591

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.315

Alfa AF: 0.251 Hom.: 6852

Bravo AF: 0.347

Asia WGS AF: 0.219 AC: 761 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	12
Dann	Benign	0.70

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: rs2680344; hg19: chr15-73653485;