rs8030574

Positions:

• chr15-73335873-C-A
• chr15-73335873-C-G

Variant summary

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

The NM_005477.3(HCN4):​c.1210-3581G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 151,760 control chromosomes in the GnomAD database, including 34,372 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 0.65 (34372 hom., cov: 30)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152

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 = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.1210-3581G>T		intron_variant		ENST00000261917.4
LOC105370890	XR_001751599.2	n.257+229C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-3581G>T		intron_variant		1	NM_005477.3	P1
	ENST00000557981.1	n.223+229C>A		intron_variant, non_coding_transcript_variant		2
	ENST00000558742.1	n.243+225C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.653 AC: 98993 AN: 151640 Hom.: 34357 Cov.: 30

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.653 AC: 99036 AN: 151760 Hom.: 34372 Cov.: 30 AF XY: 0.654 AC XY: 48506 AN XY: 74170

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.763

Gnomad4 ASJ AF: 0.720

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.703

Gnomad4 FIN AF: 0.724

Gnomad4 NFE AF: 0.765

Gnomad4 OTH AF: 0.673

Alfa AF: 0.747 Hom.: 55979

Bravo AF: 0.646

Asia WGS AF: 0.595 AC: 2073 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	1.7
DANN	Benign	0.56

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: rs8030574; hg19: chr15-73628214;