rs498005

Positions:

• chr15-73327969-C-T

Variant summary

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

The NM_005477.3(HCN4):​c.1590+1604G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 152,090 control chromosomes in the GnomAD database, including 18,346 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 0.49 (18346 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.1590+1604G>A		intron_variant		ENST00000261917.4
HCN4	XM_011521148.3	c.372+1604G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.1590+1604G>A		intron_variant		1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73953 AN: 151972 Hom.: 18339 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.486 AC: 73979 AN: 152090 Hom.: 18346 Cov.: 33 AF XY: 0.491 AC XY: 36463 AN XY: 74320

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.548

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.474

Alfa AF: 0.505 Hom.: 3292

Bravo AF: 0.475

Asia WGS AF: 0.448 AC: 1555 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.24

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: rs498005; hg19: chr15-73620310;