rs2623998

chr15-73335745-T-Cchr15-73335745-T-G

Variant summary

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

The NM_005477.3(HCN4):c.1210-3453A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 152,206 control chromosomes in the GnomAD database, including 30,553 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 0.60 (30538 hom., cov: 33)
  • Exomes 𝑓: 0.64 (15 hom.)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.603

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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.1210-3453A>G		intron_variant		ENST00000261917.4
LOC105370890	XR_001751599.2	n.257+101T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.1210-3453A>G		intron_variant		1	NM_005477.3	P1
	ENST00000557981.1	n.223+101T>C		intron_variant, non_coding_transcript_variant		2
	ENST00000558742.1	n.243+97T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91681 AN: 152016 Hom.: 30546 Cov.: 33

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.815

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.601

GnomAD4 exome AF: 0.639 AC: 46 AN: 72 Hom.: 15 AF XY: 0.656 AC XY: 42 AN XY: 64

Gnomad4 AFR exome AF: 0.250

Gnomad4 NFE exome AF: 0.672

Gnomad4 OTH exome AF: 0.600

GnomAD4 genome AF: 0.603 AC: 91690 AN: 152134 Hom.: 30538 Cov.: 33 AF XY: 0.607 AC XY: 45134 AN XY: 74364

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.635

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.815

Gnomad4 NFE AF: 0.744

Gnomad4 OTH AF: 0.597

Alfa AF: 0.704 Hom.: 52689

Bravo AF: 0.574

Asia WGS AF: 0.584 AC: 2029 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	2.0
Dann	Benign	0.46

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: rs2623998; hg19: chr15-73628086;