chr15-73366853-A-T

Position:

• chr15-73366853-A-T

Variant summary

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

The NM_005477.3(HCN4):​c.785+633T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 152,258 control chromosomes in the GnomAD database, including 61,281 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 0.90 (61281 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660

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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.785+633T>A		intron_variant		ENST00000261917.4	NP_005468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.785+633T>A		intron_variant		1	NM_005477.3	ENSP00000261917	P1

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136306 AN: 152140 Hom.: 61246 Cov.: 33

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.949

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.918

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.898

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

GnomAD4 genome AF: 0.896 AC: 136402 AN: 152258 Hom.: 61281 Cov.: 33 AF XY: 0.897 AC XY: 66724 AN XY: 74424

Gnomad4 AFR AF: 0.810

Gnomad4 AMR AF: 0.920

Gnomad4 ASJ AF: 0.949

Gnomad4 EAS AF: 0.972

Gnomad4 SAS AF: 0.918

Gnomad4 FIN AF: 0.923

Gnomad4 NFE AF: 0.928

Gnomad4 OTH AF: 0.899

Alfa AF: 0.905 Hom.: 7755

Bravo AF: 0.892

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.77

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: rs3784812; hg19: chr15-73659194;