15-73340528-C-T

Variant names:

• chr15-73340528-C-T
• rs512943
• NM_005477.3:c.1209+2857G>A

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+2857G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,092 control chromosomes in the GnomAD database, including 1,891 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 0.14 (1891 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 4 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: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Brugada syndrome 8

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 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+2857G>A		intron	N/A	NP_005468.1
	LOC105370890	NR_188273.1		n.240-485C>T		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+2857G>A		intron	N/A	ENSP00000261917.3
	ENSG00000259650	ENST00000557981.1	TSL:2	n.224-1785C>T		intron	N/A
	ENSG00000259650	ENST00000558742.1	TSL:5	n.244-485C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21387 AN: 151974 Hom.: 1884 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.141 AC: 21425 AN: 152092 Hom.: 1891 Cov.: 33 AF XY: 0.141 AC XY: 10513 AN XY: 74358

African (AFR) AF: 0.255 AC: 10556 AN: 41466

American (AMR) AF: 0.0894 AC: 1368 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 310 AN: 3472

East Asian (EAS) AF: 0.133 AC: 686 AN: 5164

South Asian (SAS) AF: 0.119 AC: 574 AN: 4812

European-Finnish (FIN) AF: 0.152 AC: 1610 AN: 10594

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0873 AC: 5937 AN: 67970

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.100 Hom.: 1198

Bravo AF: 0.142

Asia WGS AF: 0.142 AC: 493 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.019
DANN	Benign	0.49
PhyloP100		-1.8
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: rs512943; hg19: chr15-73632869;