rs12909882

Variant names:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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:10

Conservation

PhyloP100: 9.88

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 -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 id is 137539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73329605-G-A is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.0868

AC:

21817

AN:

251428

Hom.:

1094

AF XY:

0.0890

AC XY:

12090

AN XY:

135902

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 SAS exome

AF:

0.106

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

Gnomad4 AFR exome

AF:

0.0424

Gnomad4 AMR exome

AF:

0.0781

Gnomad4 ASJ exome

AF:

0.0762

Gnomad4 EAS exome

AF:

0.00229

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.129

Gnomad4 NFE exome

AF:

0.0976

Gnomad4 OTH exome

AF:

0.0828

GnomAD4 genome

AF:

0.0778

AC:

11849

AN:

152278

Hom.:

552

Cov.:

AF XY:

0.0792

AC XY:

5899

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0435

Gnomad4 AMR

AF:

0.0635

Gnomad4 ASJ

AF:

0.0855

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.0961

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.0967

Gnomad4 OTH

AF:

0.0640

Alfa

AF:

0.0880

Hom.:

271

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2017

Athena Diagnostics

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. -

PreventionGenetics, part of Exact Sciences

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

- -

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

DANN

Benign

0.80

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