15-73320492-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005477.3(HCN4):c.*1989G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,198 control chromosomes in the GnomAD database, including 52,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.81 (51998 hom., cov: 31)
  • Exomes 𝑓: 0.87 (24 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.40

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 15-73320492-C-T is Benign according to our data. Variant chr15-73320492-C-T is described in ClinVar as [Benign]. Clinvar id is 886590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.*1989G>A		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.*1989G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.*1989G>A		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122685 AN: 152018 Hom.: 51986 Cov.: 31

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.832

GnomAD4 exome AF: 0.871 AC: 54 AN: 62 Hom.: 24 Cov.: 0 AF XY: 0.854 AC XY: 41 AN XY: 48

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.957

Gnomad4 OTH exome AF: 0.833

GnomAD4 genome AF: 0.807 AC: 122733 AN: 152136 Hom.: 51998 Cov.: 31 AF XY: 0.810 AC XY: 60278 AN XY: 74392

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.911

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.822

Gnomad4 FIN AF: 0.928

Gnomad4 NFE AF: 0.932

Gnomad4 OTH AF: 0.827

Alfa AF: 0.900 Hom.: 45620

Bravo AF: 0.795

Asia WGS AF: 0.767 AC: 2666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sick sinus syndrome 2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.12
Dann	Benign	0.45

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: rs549377; hg19: chr15-73612833;