NM_005477.3:c.3600A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005477.3(HCN4):c.3600A>G(p.Pro1200Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,593,540 control chromosomes in the GnomAD database, including 678,515 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. P1200P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.88 ( 59827 hom., cov: 33)

Exomes 𝑓: 0.93 ( 618688 hom. )

Consequence

HCN4
NM_005477.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.66

Publications

23 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 15-73322493-T-C is Benign according to our data. Variant chr15-73322493-T-C is described in ClinVar as [Benign]. Clinvar id is 95285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.3600A>G	p.Pro1200Pro	synonymous_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 link	c.2382A>G	p.Pro794Pro	synonymous_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.3600A>G	p.Pro1200Pro	synonymous_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.883

AC:

134341

AN:

152096

Hom.:

59793

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.941

Gnomad ASJ

AF:

0.884

Gnomad EAS

AF:

0.880

Gnomad SAS

AF:

0.841

Gnomad FIN

AF:

0.937

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.936

Gnomad OTH

AF:

0.899

GnomAD2 exomes

AF:

0.907

AC:

196449

AN:

216572

AF XY:

0.906

show subpopulations

Gnomad AFR exome

AF:

0.748

Gnomad AMR exome

AF:

0.960

Gnomad ASJ exome

AF:

0.879

Gnomad EAS exome

AF:

0.882

Gnomad FIN exome

AF:

0.933

Gnomad NFE exome

AF:

0.932

Gnomad OTH exome

AF:

0.916

GnomAD4 exome

AF:

0.926

AC:

1334281

AN:

1441326

Hom.:

618688

Cov.:

AF XY:

0.923

AC XY:

660210

AN XY:

715248

show subpopulations

African (AFR)

AF:

0.753

AC:

24885

AN:

33040

American (AMR)

AF:

0.958

AC:

40310

AN:

42090

Ashkenazi Jewish (ASJ)

AF:

0.881

AC:

22653

AN:

25706

East Asian (EAS)

AF:

0.895

AC:

34737

AN:

38802

South Asian (SAS)

AF:

0.841

AC:

69972

AN:

83244

European-Finnish (FIN)

AF:

0.934

AC:

48045

AN:

51430

Middle Eastern (MID)

AF:

0.892

AC:

5108

AN:

5726

European-Non Finnish (NFE)

AF:

0.939

AC:

1034155

AN:

1101690

Other (OTH)

AF:

0.913

AC:

54416

AN:

59598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

5322

10644

15966

21288

26610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.883

AC:

134432

AN:

152214

Hom.:

59827

Cov.:

AF XY:

0.885

AC XY:

65848

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.765

AC:

31737

AN:

41508

American (AMR)

AF:

0.941

AC:

14403

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.884

AC:

3067

AN:

3468

East Asian (EAS)

AF:

0.880

AC:

4538

AN:

5156

South Asian (SAS)

AF:

0.841

AC:

4058

AN:

4826

European-Finnish (FIN)

AF:

0.937

AC:

9947

AN:

10616

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.936

AC:

63682

AN:

68014

Other (OTH)

AF:

0.896

AC:

1893

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

784

1568

2353

3137

3921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.911

Hom.:

42321

Bravo

AF:

0.880

Asia WGS

AF:

0.838

AC:

2915

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

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

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

- -

Dec 04, 2013

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. -

Jan 26, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

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. -

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

Mar 09, 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

-0.62

CADD

Benign

2.7

(source)

DANN

Benign

0.63

PhyloP100

-1.7

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_005477.3:c.3600A>G

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