chr15-73340528-C-T

Position:

• chr15-73340528-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.1209+2857G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,092 control chromosomes in the GnomAD database, including 1,891 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 0.14 (1891 hom., cov: 33)
• Consequence: HCN4 NM_005477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76

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]

ENSG00000259650 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3	c.1209+2857G>A		intron_variant		ENST00000261917.4	NP_005468.1
LOC105370890	NR_188273.1	n.240-485C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.1209+2857G>A		intron_variant		1	NM_005477.3	ENSP00000261917.3
ENSG00000259650	ENST00000557981.1	n.224-1785C>T		intron_variant		2
ENSG00000259650	ENST00000558742.1	n.244-485C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21387 AN: 151974 Hom.: 1884 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.141 AC: 21425 AN: 152092 Hom.: 1891 Cov.: 33 AF XY: 0.141 AC XY: 10513 AN XY: 74358

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.0894

Gnomad4 ASJ AF: 0.0893

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.0873

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0923 Hom.: 745

Bravo AF: 0.142

Asia WGS AF: 0.142 AC: 493 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.019
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs512943; hg19: chr15-73632869;