NM_005477.3:c.1210-1806G>A

Variant names:

• chr15-73334098-C-T
• rs3859014
• NM_005477.3:c.1210-1806G>A

Variant summary

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

The NM_005477.3(HCN4):​c.1210-1806G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,150 control chromosomes in the GnomAD database, including 7,918 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 (7918 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.715

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 = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1210-1806G>A		intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.-10+971G>A		intron_variant	Intron 1 of 6		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-1806G>A		intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45607 AN: 152030 Hom.: 7923 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.300 AC: 45602 AN: 152150 Hom.: 7918 Cov.: 32 AF XY: 0.302 AC XY: 22441 AN XY: 74388

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.541

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.324

Alfa AF: 0.240 Hom.: 791

Bravo AF: 0.294

Asia WGS AF: 0.389 AC: 1351 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	0.90
DANN	Benign	0.80

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: rs3859014; hg19: chr15-73626439;