NM_005477.3:c.3209G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005477.3(HCN4):c.3209G>A(p.Gly1070Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,460,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G1070G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 0.194

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

sick sinus syndrome 2, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Brugada syndrome 8
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial sick sinus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

HCN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19035429).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.3209G>A	p.Gly1070Asp	missense_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3 link	c.1991G>A	p.Gly664Asp	missense_variant	Exon 7 of 7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 link	c.3209G>A	p.Gly1070Asp	missense_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151832

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

84146

AF XY:

0.0000230

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000275

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000550

AC:

AN:

1308988

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

636626

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29822

American (AMR)

AF:

0.00

AC:

AN:

21890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19098

East Asian (EAS)

AF:

0.00

AC:

AN:

37458

South Asian (SAS)

AF:

0.00

AC:

AN:

64792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5004

European-Non Finnish (NFE)

AF:

0.0000644

AC:

AN:

1040044

Other (OTH)

AF:

0.0000920

AC:

AN:

54342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151832

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41320

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000194

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 25, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with DCM in published literature (PMID: 30847666); this patient also harbored a pathogenic variant in another cardiomyopathy-related gene; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666)

Jan 19, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HCN4: PP3

not specified

Uncertain:1

Jan 17, 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.3209G>A (p.Gly1070Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 84146 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3209G>A has been reported in the literature in individuals undergoing multigene panel testing for cardiomyopathy/arrhythmia or sudden infant death syndrome (Cazzato_2024, van Lint_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Sick Sinus Syndrome 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38849547, 30847666). ClinVar contains an entry for this variant (Variation ID: 404136). Based on the evidence outlined above, the variant was classified as uncertain significance.

Sick sinus syndrome 2, autosomal dominant

Uncertain:1

Jan 18, 2022

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Brugada syndrome 8

Uncertain:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1070 of the HCN4 protein (p.Gly1070Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 404136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HCN4 protein function with a negative predictive value of 95%. 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.

Cardiovascular phenotype

Uncertain:1

Sep 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G1070D variant (also known as c.3209G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3209. The glycine at codon 1070 is replaced by aspartic acid, an amino acid with similar properties. 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). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.19

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

0.34

PhyloP100

0.19

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.73

REVEL

Benign

0.23

Sift

Benign

0.058

Sift4G

Benign

0.086

Vest4

0.21

ClinPred

0.30

GERP RS

0.66

Varity_R

0.14

gMVP

0.34

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over