rs12440104

Positions:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000261917.4(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 ENST00000261917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.785+6818C>T		intron_variant		ENST00000261917.4	NP_005468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.785+6818C>T		intron_variant		1	NM_005477.3	ENSP00000261917	P1

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

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.412

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.299

Alfa AF: 0.350 Hom.: 7484

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12440104; hg19: chr15-73653009;