rs139590882

Positions:

• chr15-73329645-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005477.3(HCN4):​c.1518C>T​(p.Tyr506=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,194 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (15 hom.)
• Consequence: HCN4 NM_005477.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.614

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-73329645-G-A is Benign according to our data. Variant chr15-73329645-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73329645-G-A is described in Lovd as [Benign]. Variant chr15-73329645-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.614 with no splicing effect.
• BS2: High AC in GnomAd4 at 241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.1518C>T	p.Tyr506=	synonymous_variant	4/8	ENST00000261917.4
HCN4	XM_011521148.3	c.300C>T	p.Tyr100=	synonymous_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.1518C>T	p.Tyr506=	synonymous_variant	4/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00229 AC: 575 AN: 251466 Hom.: 2 AF XY: 0.00228 AC XY: 310 AN XY: 135906

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00207 AC: 3028 AN: 1461862 Hom.: 15 Cov.: 32 AF XY: 0.00208 AC XY: 1511 AN XY: 727236

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152332 Hom.: 0 Cov.: 34 AF XY: 0.00149 AC XY: 111 AN XY: 74478

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00314 Hom.: 1

Bravo AF: 0.00188

EpiCase AF: 0.00245

EpiControl AF: 0.00207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	HCN4: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Brugada syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

HCN4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.8
DANN	Benign	0.73

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: rs139590882; hg19: chr15-73621986; COSMIC: COSV56081941;