rs560874115

Positions:

• chr15-73367813-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005477.3(HCN4):​c.458A>G​(p.Glu153Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,237,616 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11
• Conservation: PhyloP100: -0.0980

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036761194).
• BP6: Variant 15-73367813-T-C is Benign according to our data. Variant chr15-73367813-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180370.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5, Benign=1}. Variant chr15-73367813-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.458A>G	p.Glu153Gly	missense_variant	1/8	ENST00000261917.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.458A>G	p.Glu153Gly	missense_variant	1/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 212 AN: 150518 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000595

Gnomad ASJ AF: 0.00783

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000298

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00233

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00206 AC: 3 AN: 1454 Hom.: 0 AF XY: 0.00350 AC XY: 3 AN XY: 858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00300 AC: 3262 AN: 1086990 Hom.: 7 Cov.: 31 AF XY: 0.00300 AC XY: 1555 AN XY: 518372

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.000389

Gnomad4 ASJ exome AF: 0.00457

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.00333

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00141 AC: 212 AN: 150626 Hom.: 0 Cov.: 33 AF XY: 0.00135 AC XY: 99 AN XY: 73602

Gnomad4 AFR AF: 0.000363

Gnomad4 AMR AF: 0.000594

Gnomad4 ASJ AF: 0.00783

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000298

Gnomad4 NFE AF: 0.00233

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00143

ExAC AF: 0.000137 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	This variant is associated with the following publications: (PMID: 29588962, 28341588, 30847666) -
Likely 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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	HCN4: PP3, BS1, BS2 -

Sick sinus syndrome 2, autosomal dominant Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

HCN4 NM_005477.2 exon 1 p.Glu153Gly (c.458A>G): This variant has been reported in the literature in one individual with genearlized epilepsy and in one individual with unspecified cardiac arrhythmia (Becker 2017 PMID:29588962, Proost 2017 PMID:28341588). This variant did not segregate with disease in at least four affected family members with epilepsy (Becker 2017 PMID:29588962). This variant is present in 0.1% (31/14734) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-73660154-T-C). This variant is present in ClinVar (Variation ID:180370). This variant amino acid Glycine (Gly) is present in several bird and fish species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. However, an in vitro functional study using voltage clamp anaylsis does predict that this variant will impact the protein by causing a hyperpolarizing shift in activation and reduced current amplitudes (Becker 2017 PMID:29588962). However, this study may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Brugada syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 28, 2014

- -

Primary dilated cardiomyopathy;C0878544:Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 11, 2019

- -

HCN4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2022

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

Brugada syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2018

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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.037	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.19	N
REVEL	Benign	0.19
Sift	Benign	0.073	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.049
MVP		0.69
MPC		1.3
ClinPred		0.037	T
GERP RS		3.7
Varity_R		0.036
gMVP		0.31

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: rs560874115; hg19: chr15-73660154;