rs548525

Variant names:

• chr15-73335530-C-G
• rs548525
• NM_005477.3:c.1210-3238G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• sick sinus syndrome 2, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Brugada syndrome 8

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000259650 (HGNC:58475):

LOC105370890 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005477.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	NM_005477.3	MANE Select	c.1210-3238G>C		intron	N/A	NP_005468.1	Q9Y3Q4
	LOC105370890	NR_188273.1		n.125C>G		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.1210-3238G>C		intron	N/A	ENSP00000261917.3	Q9Y3Q4
	ENSG00000259650	ENST00000557981.1	TSL:2	n.109C>G		non_coding_transcript_exon	Exon 2 of 3
	ENSG00000259650	ENST00000558742.1	TSL:5	n.125C>G		non_coding_transcript_exon	Exon 2 of 4

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.800 AC: 8 AN: 10

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.833 AC: 55 AN: 66

Other (OTH) AF: 0.750 AC: 3 AN: 4

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

African (AFR) AF: 0.750 AC: 31148 AN: 41542

American (AMR) AF: 0.910 AC: 13927 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3047 AN: 3472

East Asian (EAS) AF: 0.806 AC: 4166 AN: 5166

South Asian (SAS) AF: 0.807 AC: 3898 AN: 4832

European-Finnish (FIN) AF: 0.824 AC: 8741 AN: 10612

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.887 AC: 60342 AN: 68012

Other (OTH) AF: 0.853 AC: 1806 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.9
DANN	Benign	0.55
PhyloP100		0.017
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs548525; hg19: chr15-73627871;