15-73323079-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_005477.3(HCN4):c.3014C>G(p.Ser1005Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000987 in 1,418,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. S1005F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.31

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3669492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3	c.3014C>G	p.Ser1005Cys	missense_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3	c.1796C>G	p.Ser599Cys	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4	c.3014C>G	p.Ser1005Cys	missense_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000987 AC: 14 AN: 1418600 Hom.: 0 Cov.: 34 AF XY: 0.00000570 AC XY: 4 AN XY: 702156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

Brugada syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2021

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. This variant has not been reported in the literature in individuals affected with HCN4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1005 of the HCN4 protein (p.Ser1005Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	13
Dann	Benign	0.91
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.10	T
Polyphen		0.69	P
Vest4		0.12
MutPred		0.25		Loss of glycosylation at S1005 (P = 0.0067);
MVP		0.79
MPC		0.17
ClinPred		0.18	T
GERP RS		2.8
Varity_R		0.072
gMVP		0.53

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

Other links and lift over

dbSNP: rs780624939; hg19: chr15-73615420;