15-73323229-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005477.3(HCN4):c.2864C>G(p.Pro955Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P955L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.23

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12730816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.2864C>G	p.Pro955Arg	missense_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3 link	c.1646C>G	p.Pro549Arg	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.2864C>G	p.Pro955Arg	missense_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000668

AC:

AN:

149646

AF XY:

0.0000124

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000148

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1375692

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

674750

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31642

American (AMR)

AF:

0.00

AC:

AN:

33820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21554

East Asian (EAS)

AF:

0.00

AC:

AN:

38380

South Asian (SAS)

AF:

0.00

AC:

AN:

73022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1071390

Other (OTH)

AF:

0.00

AC:

AN:

56864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 18, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Brugada syndrome 8

Uncertain:1

Mar 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 1479789). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 955 of the HCN4 protein (p.Pro955Arg).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0034

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.21

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.36

REVEL

Uncertain

0.31

Sift

Uncertain

0.025

Sift4G

Benign

0.27

Vest4

0.044

ClinPred

0.024

GERP RS

-1.3

Varity_R

0.057

gMVP

0.28

Mutation Taster

=97/3

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over