rs12440104

Variant names:

• chr15-73360668-G-A
• rs12440104
• NM_005477.3:c.785+6818C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-73360668-G-A
• chr15-73360668-G-T

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+6818C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,032 control chromosomes in the GnomAD database, including 7,759 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 0.30 (7759 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 5 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.785+6818C>T		intron_variant	Intron 1 of 7	ENST00000261917.4	NP_005468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.785+6818C>T		intron_variant	Intron 1 of 7	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45368 AN: 151912 Hom.: 7764 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.300

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

GnomAD4 genome AF: 0.298 AC: 45359 AN: 152032 Hom.: 7759 Cov.: 32 AF XY: 0.295 AC XY: 21885 AN XY: 74312

African (AFR) AF: 0.130 AC: 5392 AN: 41470

American (AMR) AF: 0.326 AC: 4987 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3468

East Asian (EAS) AF: 0.412 AC: 2126 AN: 5160

South Asian (SAS) AF: 0.306 AC: 1476 AN: 4820

European-Finnish (FIN) AF: 0.298 AC: 3148 AN: 10564

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25881 AN: 67956

Other (OTH) AF: 0.299 AC: 631 AN: 2110

Alfa AF: 0.349 Hom.: 8698

Bravo AF: 0.296

Asia WGS AF: 0.322 AC: 1118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.77
PhyloP100		-0.22
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: rs12440104; hg19: chr15-73653009;