15-73323289-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_005477.3(HCN4):c.2804C>A(p.Ser935Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000305 in 1,538,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S935F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.30

Publications

2 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=0.29654223).

BP6

Variant 15-73323289-G-T is Benign according to our data. Variant chr15-73323289-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 470659.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.2804C>A	p.Ser935Tyr	missense_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3 link	c.1586C>A	p.Ser529Tyr	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.2804C>A	p.Ser935Tyr	missense_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000407

AC:

AN:

147356

AF XY:

0.0000380

show subpopulations

Gnomad AFR exome

AF:

0.000582

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:

0.0000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1386834

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

681080

show subpopulations

African (AFR)

AF:

0.000559

AC:

AN:

32202

American (AMR)

AF:

0.00

AC:

AN:

34870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23420

East Asian (EAS)

AF:

0.00

AC:

AN:

37388

South Asian (SAS)

AF:

0.00

AC:

AN:

76394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1073182

Other (OTH)

AF:

0.0000697

AC:

AN:

57408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000158

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000507

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.0000348

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 02, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified through a testing cohort of individuals who suffered unexplained natural deaths; patient-specific details were not described (PMID: 30578647); Functional studies showed that p.(S935Y) failed to affect channel function or localization (PMID: 30578647); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119, 30578647)

Cardiovascular phenotype

Uncertain:1

Aug 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S935Y variant (also known as c.2804C>A), located in coding exon 8 of the HCN4 gene, results from a C to A substitution at nucleotide position 2804. The serine at codon 935 is replaced by tyrosine, an amino acid with dissimilar properties. This variant was detected in a sudden death victim; however, details were limited, and in vitro studies by one group suggested this variant may not impact protein function (Dong J et al. Pacing Clin Electrophysiol, 2019 02;42:275-282). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Brugada syndrome 8

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.30

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

0.69

PhyloP100

6.3

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.43

Sift

Uncertain

0.0090

Sift4G

Benign

0.14

Vest4

0.23

ClinPred

0.095

GERP RS

2.9

Varity_R

0.17

gMVP

0.32

Mutation Taster

=77/23

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