rs2623997

Variant names:

• chr15-73336373-T-C
• rs2623997
• NM_005477.3:c.1210-4081A>G

Variant summary

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

The ENST00000261917.4(HCN4):​c.1210-4081A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,968 control chromosomes in the GnomAD database, including 16,313 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 0.46 (16313 hom., cov: 32)
• Consequence: HCN4 ENST00000261917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• 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: 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261917.4. 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.1210-4081A>G		intron	N/A	NP_005468.1
	LOC105370890	NR_188273.1		n.239+729T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.1210-4081A>G		intron	N/A	ENSP00000261917.3
	ENSG00000259650	ENST00000557981.1	TSL:2	n.223+729T>C		intron	N/A
	ENSG00000259650	ENST00000558742.1	TSL:5	n.243+725T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69849 AN: 151850 Hom.: 16312 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.458

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

GnomAD4 genome AF: 0.460 AC: 69870 AN: 151968 Hom.: 16313 Cov.: 32 AF XY: 0.454 AC XY: 33753 AN XY: 74268

African (AFR) AF: 0.385 AC: 15981 AN: 41464

American (AMR) AF: 0.456 AC: 6971 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1720 AN: 3472

East Asian (EAS) AF: 0.532 AC: 2742 AN: 5152

South Asian (SAS) AF: 0.396 AC: 1904 AN: 4806

European-Finnish (FIN) AF: 0.432 AC: 4563 AN: 10558

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34433 AN: 67926

Other (OTH) AF: 0.458 AC: 965 AN: 2108

Alfa AF: 0.488 Hom.: 25872

Bravo AF: 0.463

Asia WGS AF: 0.421 AC: 1460 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.69
PhyloP100		-0.10
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: rs2623997; hg19: chr15-73628714;