rs498005

Variant names:

• chr15-73327969-C-T
• rs498005
• NM_005477.3:c.1590+1604G>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.1590+1604G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 152,090 control chromosomes in the GnomAD database, including 18,346 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 0.49 (18346 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1590+1604G>A		intron_variant	Intron 4 of 7	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.372+1604G>A		intron_variant	Intron 3 of 6		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1590+1604G>A		intron_variant	Intron 4 of 7	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73953 AN: 151972 Hom.: 18339 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.486 AC: 73979 AN: 152090 Hom.: 18346 Cov.: 33 AF XY: 0.491 AC XY: 36463 AN XY: 74320

African (AFR) AF: 0.399 AC: 16568 AN: 41482

American (AMR) AF: 0.464 AC: 7091 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2020 AN: 3468

East Asian (EAS) AF: 0.548 AC: 2811 AN: 5130

South Asian (SAS) AF: 0.484 AC: 2334 AN: 4818

European-Finnish (FIN) AF: 0.591 AC: 6266 AN: 10600

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35184 AN: 67984

Other (OTH) AF: 0.474 AC: 1001 AN: 2112

Alfa AF: 0.502 Hom.: 3351

Bravo AF: 0.475

Asia WGS AF: 0.448 AC: 1555 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.24
PhyloP100		-1.6
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: rs498005; hg19: chr15-73620310;