15-73321773-T-C

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.*708A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 153,422 control chromosomes in the GnomAD database, including 54,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.83 (54167 hom., cov: 32)
  • Exomes 𝑓: 0.91 (536 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.13

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=-0.96).
• BP6: Variant 15-73321773-T-C is Benign according to our data. Variant chr15-73321773-T-C is described in ClinVar as [Benign]. Clinvar id is 884688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.*708A>G		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.*708A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.*708A>G		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.829 AC: 126088 AN: 152012 Hom.: 54155 Cov.: 32

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.921

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.852

GnomAD4 exome AF: 0.913 AC: 1179 AN: 1292 Hom.: 536 Cov.: 0 AF XY: 0.920 AC XY: 675 AN XY: 734

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.922

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.857

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.930

Gnomad4 NFE exome AF: 0.905

Gnomad4 OTH exome AF: 0.950

GnomAD4 genome AF: 0.829 AC: 126146 AN: 152130 Hom.: 54167 Cov.: 32 AF XY: 0.833 AC XY: 61948 AN XY: 74376

Gnomad4 AFR AF: 0.581

Gnomad4 AMR AF: 0.921

Gnomad4 ASJ AF: 0.884

Gnomad4 EAS AF: 0.866

Gnomad4 SAS AF: 0.830

Gnomad4 FIN AF: 0.939

Gnomad4 NFE AF: 0.935

Gnomad4 OTH AF: 0.848

Alfa AF: 0.879 Hom.: 7036

Bravo AF: 0.819

Asia WGS AF: 0.810 AC: 2816 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	-0.96
Cadd	Benign	0.017
Dann	Benign	0.35

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: rs2623999; hg19: chr15-73614114;