15-73357252-C-T

Variant names:

• chr15-73357252-C-T
• rs477377
• NM_005477.3:c.785+10234G>A

Variant summary

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

The NM_005477.3(HCN4):​c.785+10234G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,208 control chromosomes in the GnomAD database, including 1,010 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 0.10 (1010 hom., cov: 32)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.780

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.785+10234G>A		intron_variant	Intron 1 of 7	ENST00000261917.4	NP_005468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.785+10234G>A		intron_variant	Intron 1 of 7	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15834 AN: 152090 Hom.: 1011 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.0839

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0727

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.104 AC: 15856 AN: 152208 Hom.: 1010 Cov.: 32 AF XY: 0.103 AC XY: 7703 AN XY: 74426

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.0841

Gnomad4 FIN AF: 0.0776

Gnomad4 NFE AF: 0.0726

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0783 Hom.: 677

Bravo AF: 0.108

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.7
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: rs477377; hg19: chr15-73649593;