rs3826046

chr15-73358483-G-Achr15-73358483-G-C

Variant summary

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

The NM_005477.3(HCN4):c.785+9003C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,196 control chromosomes in the GnomAD database, including 1,318 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 0.11 (1318 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.797

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=-0.56).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.785+9003C>T		intron_variant		ENST00000261917.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.785+9003C>T		intron_variant		1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16015 AN: 152076 Hom.: 1319 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.105 AC: 16011 AN: 152196 Hom.: 1318 Cov.: 32 AF XY: 0.107 AC XY: 7971 AN XY: 74380

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.134

Alfa AF: 0.101 Hom.: 529

Bravo AF: 0.114

Asia WGS AF: 0.243 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	5.1
Dann	Benign	0.72

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: rs3826046; hg19: chr15-73650824;