rs11857639

Positions:

• chr15-73345431-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.786-1623G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 152,250 control chromosomes in the GnomAD database, including 466 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 0.067 (466 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39

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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.786-1623G>A		intron_variant		ENST00000261917.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.786-1623G>A		intron_variant		1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10154 AN: 152132 Hom.: 463 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0924

Gnomad OTH AF: 0.0756

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

GnomAD4 genome AF: 0.0667 AC: 10161 AN: 152250 Hom.: 466 Cov.: 32 AF XY: 0.0662 AC XY: 4931 AN XY: 74436

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0632

Gnomad4 NFE AF: 0.0924

Gnomad4 OTH AF: 0.0739

Alfa AF: 0.0888 Hom.: 302

Bravo AF: 0.0662

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.65

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: rs11857639; hg19: chr15-73637772;