15-73321847-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005477.3(HCN4):c.*634C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 156,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46

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=-0.8).
• BP6: Variant 15-73321847-G-A is Benign according to our data. Variant chr15-73321847-G-A is described in ClinVar as [Benign]. Clinvar id is 884689.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00328 (500/152358) while in subpopulation SAS AF= 0.0141 (68/4834). AF 95% confidence interval is 0.0114. There are 1 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.*634C>T		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.*634C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.*634C>T		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00810

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00176 AC: 8 AN: 4550 Hom.: 0 Cov.: 0 AF XY: 0.00124 AC XY: 3 AN XY: 2420

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.00488

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00427

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000725

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00328 AC: 500 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74516

Gnomad4 AFR AF: 0.00810

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00277 Hom.: 0

Bravo AF: 0.00351

Asia WGS AF: 0.00606 AC: 22 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	-0.80
Cadd	Benign	0.31
Dann	Benign	0.80

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: rs138059941; hg19: chr15-73614188;