rs524457

chr15-73320036-G-A

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.*2445C>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 0.0971 in 152,264 control chromosomes in the GnomAD database, including 983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.097 (983 hom., cov: 32)
  • Exomes 𝑓: 0.043 (0 hom.)
• Consequence: HCN4 NM_005477.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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=-0.83).
• BP6: Variant 15-73320036-G-A is Benign according to our data. Variant chr15-73320036-G-A is described in ClinVar as [Benign]. Clinvar id is 885566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.*2445C>T		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.*2445C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.*2445C>T		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.0971 AC: 14765 AN: 152052 Hom.: 981 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0663

Gnomad OTH AF: 0.0783

GnomAD4 exome AF: 0.0426 AC: 4 AN: 94 Hom.: 0 Cov.: 0 AF XY: 0.0179 AC XY: 1 AN XY: 56

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0971 AC: 14774 AN: 152170 Hom.: 983 Cov.: 32 AF XY: 0.0977 AC XY: 7266 AN XY: 74394

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.0663

Gnomad4 OTH AF: 0.0770

Alfa AF: 0.0677 Hom.: 787

Bravo AF: 0.0971

Asia WGS AF: 0.0140 AC: 50 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	-0.83
Cadd	Benign	11
Dann	Benign	0.41

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: rs524457; hg19: chr15-73612377;