rs478438

Positions:

• chr15-73338345-G-A
• chr15-73338345-G-C

Variant summary

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

The NM_005477.3(HCN4):​c.1209+5040C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,184 control chromosomes in the GnomAD database, including 6,066 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 0.22 (6066 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1209+5040C>T		intron_variant		ENST00000261917.4	NP_005468.1
LOC105370890	XR_001751599.2	n.257+2701G>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+5040C>T		intron_variant		1	NM_005477.3	ENSP00000261917	P1
	ENST00000557981.1	n.223+2701G>A		intron_variant, non_coding_transcript_variant		2
	ENST00000558742.1	n.244-2668G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32940 AN: 152066 Hom.: 6029 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0939

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.217 AC: 33029 AN: 152184 Hom.: 6066 Cov.: 33 AF XY: 0.215 AC XY: 16001 AN XY: 74414

Gnomad4 AFR AF: 0.503

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0894

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.0939

Gnomad4 OTH AF: 0.181

Alfa AF: 0.120 Hom.: 940

Bravo AF: 0.227

Asia WGS AF: 0.186 AC: 645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.0
DANN	Benign	0.37

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: rs478438; hg19: chr15-73630686;