rs548525

Positions:

• chr15-73335530-C-G

Variant summary

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

The NM_005477.3(HCN4):​c.1210-3238G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.842 in 152,350 control chromosomes in the GnomAD database, including 54,318 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 0.84 (54290 hom., cov: 35)
  • Exomes 𝑓: 0.83 (28 hom.)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1210-3238G>C		intron_variant		ENST00000261917.4	NP_005468.1
LOC105370890	XR_001751599.2	n.143C>G		non_coding_transcript_exon_variant	2/3
HCN4	XM_011521148.3			upstream_gene_variant			XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-3238G>C		intron_variant		1	NM_005477.3	ENSP00000261917	P1
	ENST00000557981.1	n.109C>G		non_coding_transcript_exon_variant	2/3	2
	ENST00000558742.1	n.125C>G		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.842 AC: 128091 AN: 152150 Hom.: 54244 Cov.: 35

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.909

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.855

GnomAD4 exome AF: 0.829 AC: 68 AN: 82 Hom.: 28 Cov.: 0 AF XY: 0.813 AC XY: 52 AN XY: 64

Gnomad4 FIN exome AF: 0.800

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.842 AC: 128194 AN: 152268 Hom.: 54290 Cov.: 35 AF XY: 0.840 AC XY: 62563 AN XY: 74440

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.910

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.807

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.887

Gnomad4 OTH AF: 0.853

Alfa AF: 0.863 Hom.: 6237

Bravo AF: 0.846

Asia WGS AF: 0.793 AC: 2759 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.9
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs548525; hg19: chr15-73627871;