rs4776632

Positions:

• chr15-73340035-G-A

Variant summary

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

The NM_005477.3(HCN4):​c.1209+3350C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,108 control chromosomes in the GnomAD database, including 11,115 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 0.36 (11115 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1209+3350C>T		intron_variant		ENST00000261917.4	NP_005468.1
LOC105370890	XR_001751599.2	n.258-2278G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1209+3350C>T		intron_variant		1	NM_005477.3	ENSP00000261917	P1
	ENST00000557981.1	n.224-2278G>A		intron_variant, non_coding_transcript_variant		2
	ENST00000558742.1	n.244-978G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54179 AN: 151988 Hom.: 11120 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.374

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

GnomAD4 genome AF: 0.356 AC: 54172 AN: 152108 Hom.: 11115 Cov.: 32 AF XY: 0.355 AC XY: 26410 AN XY: 74350

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.406

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.373

Alfa AF: 0.387 Hom.: 1533

Bravo AF: 0.355

Asia WGS AF: 0.340 AC: 1183 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	2.4
DANN	Benign	0.53

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: rs4776632; hg19: chr15-73632376;