rs370884239

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_005477.3(HCN4):c.1636G>A(p.Asp546Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D546D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.96

Variant links:

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]

HCN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.1636G>A	p.Asp546Asn	missense_variant	Exon 5 of 8	ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 link	c.418G>A	p.Asp140Asn	missense_variant	Exon 4 of 7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 link	c.1636G>A	p.Asp546Asn	missense_variant	Exon 5 of 8	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251434

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135894

show subpopulations

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:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000171

AC:

250

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000211

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.0000800

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:2

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D546N variant (also known as c.1636G>A), located in coding exon 5 of the HCN4 gene, results from a G to A substitution at nucleotide position 1636. The aspartic acid at codon 546 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in a sudden unexplained death case; however, clinical information was limited (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10). This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). Limited functional studies showed that p.D546N does not affect surface expression or cellular protein concentration, but it may have some impact on the channel open state and response to cAMP (Dong J et al. Pacing Clin Electrophysiol, 2019 02;42:275-282). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Mar 11, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HCN4 c.1636G>A (p.Asp546Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251434 control chromosomes. The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in HCN4 causing Sick Sinus Syndrome 2 phenotype (1e-05). c.1636G>A has been reported in the literature in an individual affected with Sudden Death (Lin_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Sick Sinus Syndrome 2. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Dong_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30578647, 29247119). ClinVar contains an entry for this variant (Variation ID: 470650). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Jul 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with sudden infant death syndrome (PMID: 29247119, 30578647); Functional studies suggest the presence of this variant may alter channel function; however, it is not known whether these findings are clinically relevant in vivo (PMID: 30578647); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30391667, 30578647, 30847666, 29247119) -

Brugada syndrome 8

Uncertain:1

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 546 of the HCN4 protein (p.Asp546Asn). This variant is present in population databases (rs370884239, gnomAD 0.01%). This missense change has been observed in individual(s) with HCN4-related conditions (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 470650). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HCN4 function (PMID: 30578647). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.58

Sift

Uncertain

0.018

Sift4G

Uncertain

0.011

Polyphen

0.99

Vest4

0.63

MVP

0.95

MPC

1.1

ClinPred

0.61

GERP RS

3.3

Varity_R

0.55

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over