rs4776632

Variant names:

• chr15-73340035-G-A
• rs4776632
• NM_005477.3:c.1209+3350C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005477.3(HCN4):​c.1209+3350C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,108 control chromosomes in the GnomAD database, including 11,115 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 0.36 (11115 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 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.1209+3350C>T		intron	N/A	NP_005468.1	Q9Y3Q4
	LOC105370890	NR_188273.1		n.240-978G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.1209+3350C>T		intron	N/A	ENSP00000261917.3	Q9Y3Q4
	ENSG00000259650	ENST00000557981.1	TSL:2	n.224-2278G>A		intron	N/A
	ENSG00000259650	ENST00000558742.1	TSL:5	n.244-978G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54179 AN: 151988 Hom.: 11120 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.374

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

GnomAD4 genome AF: 0.356 AC: 54172 AN: 152108 Hom.: 11115 Cov.: 32 AF XY: 0.355 AC XY: 26410 AN XY: 74350

African (AFR) AF: 0.144 AC: 5995 AN: 41546

American (AMR) AF: 0.450 AC: 6884 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3470

East Asian (EAS) AF: 0.406 AC: 2094 AN: 5164

South Asian (SAS) AF: 0.354 AC: 1700 AN: 4808

European-Finnish (FIN) AF: 0.371 AC: 3926 AN: 10574

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30759 AN: 67952

Other (OTH) AF: 0.373 AC: 786 AN: 2108

Alfa AF: 0.378 Hom.: 1543

Bravo AF: 0.355

Asia WGS AF: 0.340 AC: 1183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4776632; hg19: chr15-73632376;