rs12909882

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005477.3(HCN4):c.1558C>T(p.Leu520Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0922 in 1,614,036 control chromosomes in the GnomAD database, including 7,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L520L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.078 ( 552 hom., cov: 34)

Exomes 𝑓: 0.094 ( 6808 hom. )

Consequence

HCN4
NM_005477.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.88

Publications

11 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: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 15-73329605-G-A is Benign according to our data. Variant chr15-73329605-G-A is described in ClinVar as Benign. ClinVar VariationId is 137539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.1558C>T	p.Leu520Leu	synonymous_variant	Exon 4 of 8	ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 link	c.340C>T	p.Leu114Leu	synonymous_variant	Exon 3 of 7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 link	c.1558C>T	p.Leu520Leu	synonymous_variant	Exon 4 of 8	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0779

AC:

11851

AN:

152160

Hom.:

554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0435

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0635

Gnomad ASJ

AF:

0.0855

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0971

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0967

Gnomad OTH

AF:

0.0651

GnomAD2 exomes

AF:

0.0868

AC:

21817

AN:

251428

AF XY:

0.0890

show subpopulations

Gnomad AFR exome

AF:

0.0430

Gnomad AMR exome

AF:

0.0835

Gnomad ASJ exome

AF:

0.0726

Gnomad EAS exome

AF:

0.00239

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.0953

Gnomad OTH exome

AF:

0.0824

GnomAD4 exome

AF:

0.0937

AC:

136926

AN:

1461758

Hom.:

6808

Cov.:

AF XY:

0.0942

AC XY:

68517

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0424

AC:

1421

AN:

33480

American (AMR)

AF:

0.0781

AC:

3491

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0762

AC:

1992

AN:

26132

East Asian (EAS)

AF:

0.00229

AC:

AN:

39700

South Asian (SAS)

AF:

0.106

AC:

9149

AN:

86254

European-Finnish (FIN)

AF:

0.129

AC:

6872

AN:

53416

Middle Eastern (MID)

AF:

0.0640

AC:

368

AN:

5752

European-Non Finnish (NFE)

AF:

0.0976

AC:

108540

AN:

1111924

Other (OTH)

AF:

0.0828

AC:

5002

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7329

14658

21988

29317

36646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3932

7864

11796

15728

19660

<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:

0.0778

AC:

11849

AN:

152278

Hom.:

552

Cov.:

AF XY:

0.0792

AC XY:

5899

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0435

AC:

1808

AN:

41570

American (AMR)

AF:

0.0635

AC:

972

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0855

AC:

297

AN:

3472

East Asian (EAS)

AF:

0.00347

AC:

AN:

5180

South Asian (SAS)

AF:

0.0961

AC:

464

AN:

4826

European-Finnish (FIN)

AF:

0.137

AC:

1457

AN:

10608

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0967

AC:

6573

AN:

68000

Other (OTH)

AF:

0.0640

AC:

135

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

582

1164

1747

2329

2911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0885

Hom.:

373

Bravo

AF:

0.0691

Asia WGS

AF:

0.0390

AC:

134

AN:

3478

EpiCase

AF:

0.0914

EpiControl

AF:

0.0883

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 10, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sick sinus syndrome 2, autosomal dominant

Benign:1

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Brugada syndrome 8

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 23, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

-0.41

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

9.9

Mutation Taster

=16/84

polymorphism (auto)

(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