rs8030574

Variant names:

• chr15-73335873-C-A
• rs8030574
• NM_005477.3:c.1210-3581G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-73335873-C-A
• chr15-73335873-C-G

Variant summary

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

The NM_005477.3(HCN4):​c.1210-3581G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 151,760 control chromosomes in the GnomAD database, including 34,372 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 0.65 (34372 hom., cov: 30)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• 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: 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1210-3581G>T		intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1
LOC105370890	NR_188273.1	n.239+229C>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-3581G>T		intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3
ENSG00000259650	ENST00000557981.1	n.223+229C>A		intron_variant	Intron 2 of 2	2
ENSG00000259650	ENST00000558742.1	n.243+225C>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.653 AC: 98993 AN: 151640 Hom.: 34357 Cov.: 30

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.653 AC: 99036 AN: 151760 Hom.: 34372 Cov.: 30 AF XY: 0.654 AC XY: 48506 AN XY: 74170

African (AFR) AF: 0.400 AC: 16524 AN: 41360

American (AMR) AF: 0.763 AC: 11649 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2500 AN: 3470

East Asian (EAS) AF: 0.588 AC: 3006 AN: 5114

South Asian (SAS) AF: 0.703 AC: 3368 AN: 4792

European-Finnish (FIN) AF: 0.724 AC: 7640 AN: 10556

Middle Eastern (MID) AF: 0.762 AC: 221 AN: 290

European-Non Finnish (NFE) AF: 0.765 AC: 51932 AN: 67894

Other (OTH) AF: 0.673 AC: 1417 AN: 2104

Alfa AF: 0.731 Hom.: 75746

Bravo AF: 0.646

Asia WGS AF: 0.595 AC: 2073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.56
PhyloP100		-0.15
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: rs8030574; hg19: chr15-73628214;