rs560874115

Positions:

chr15-73367813-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:12

Conservation

PhyloP100: -0.0980

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 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: {Likely_benign=5, Benign=1, Uncertain_significance=3}. 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	Protein	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.458A>G	p.Glu153Gly	missense_variant	1/8	ENST00000261917.4	NP_005468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.458A>G	p.Glu153Gly	missense_variant	1/8	1	NM_005477.3	ENSP00000261917	P1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

212

AN:

150518

Hom.:

Cov.:

show subpopulations

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:

AN:

1454

Hom.:

AF XY:

0.00350

AC XY:

AN XY:

858

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:

0.00259

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00300

AC:

3262

AN:

1086990

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

1555

AN XY:

518372

show subpopulations

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.:

Cov.:

AF XY:

0.00135

AC XY:

AN XY:

73602

show subpopulations

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.:

Bravo

AF:

0.00143

ExAC

AF:

0.000137

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:7

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

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

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 07, 2024

Variant summary: HCN4 c.458A>G (p.Glu153Gly) 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 0.0028 in 1237616 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 269 fold of the estimated maximal expected allele frequency for a pathogenic variant in HCN4 causing Sick Sinus Syndrome 2 phenotype (1e-05), strongly suggesting that the variant is benign. ClinVar contains an entry for this variant (Variation ID: 180370). Based on the evidence outlined above, the variant was classified as likely benign. -

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

- -

Brugada syndrome 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

HCN4-related disorder

Benign:1

Likely benign, no assertion criteria provided

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). -

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.22

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.037

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.19

REVEL

Benign

0.19

Sift

Benign

0.073

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.049

MVP

0.69

MPC

1.3

ClinPred

0.037

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

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