rs478438

Variant names:

• chr15-73338345-G-A
• rs478438
• NM_005477.3:c.1209+5040C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-73338345-G-A
• chr15-73338345-G-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.1209+5040C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,184 control chromosomes in the GnomAD database, including 6,066 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 0.22 (6066 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1209+5040C>T		intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1
LOC105370890	NR_188273.1	n.240-2668G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1209+5040C>T		intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3
ENSG00000259650	ENST00000557981.1	n.223+2701G>A		intron_variant	Intron 2 of 2	2
ENSG00000259650	ENST00000558742.1	n.244-2668G>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32940 AN: 152066 Hom.: 6029 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0939

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.217 AC: 33029 AN: 152184 Hom.: 6066 Cov.: 33 AF XY: 0.215 AC XY: 16001 AN XY: 74414

African (AFR) AF: 0.503 AC: 20872 AN: 41490

American (AMR) AF: 0.119 AC: 1815 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 310 AN: 3468

East Asian (EAS) AF: 0.152 AC: 786 AN: 5184

South Asian (SAS) AF: 0.132 AC: 636 AN: 4820

European-Finnish (FIN) AF: 0.160 AC: 1693 AN: 10602

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0939 AC: 6387 AN: 68012

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.118 Hom.: 1004

Bravo AF: 0.227

Asia WGS AF: 0.186 AC: 645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.0
DANN	Benign	0.37
PhyloP100		0.39
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: rs478438; hg19: chr15-73630686;