15-73361144-A-G

Variant names:

• chr15-73361144-A-G
• rs2680344
• NM_005477.3:c.785+6342T>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.785+6342T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,056 control chromosomes in the GnomAD database, including 10,602 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 0.34 (10602 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	NM_005477.3	MANE Select	c.785+6342T>C		intron	N/A	NP_005468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.785+6342T>C		intron	N/A	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51356 AN: 151938 Hom.: 10558 Cov.: 33

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.338 AC: 51460 AN: 152056 Hom.: 10602 Cov.: 33 AF XY: 0.337 AC XY: 25078 AN XY: 74324

African (AFR) AF: 0.591 AC: 24492 AN: 41462

American (AMR) AF: 0.276 AC: 4214 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 799 AN: 3466

East Asian (EAS) AF: 0.138 AC: 715 AN: 5176

South Asian (SAS) AF: 0.199 AC: 958 AN: 4824

European-Finnish (FIN) AF: 0.306 AC: 3232 AN: 10570

Middle Eastern (MID) AF: 0.321 AC: 93 AN: 290

European-Non Finnish (NFE) AF: 0.237 AC: 16125 AN: 67972

Other (OTH) AF: 0.315 AC: 663 AN: 2108

Alfa AF: 0.266 Hom.: 18576

Bravo AF: 0.347

Asia WGS AF: 0.219 AC: 761 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		-0.013
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: rs2680344; hg19: chr15-73653485;