chr15-73323235-C-T

Variant names:

• chr15-73323235-C-T
• rs1555475226
• NM_005477.3:c.2858G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005477.3(HCN4):​c.2858G>A​(p.Gly953Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.2858G>A	p.Gly953Glu	missense_variant	Exon 8 of 8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3	c.1640G>A	p.Gly547Glu	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	c.2858G>A	p.Gly953Glu	missense_variant	Exon 8 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374460 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 673986

African (AFR) AF: 0.00 AC: 0 AN: 31744

American (AMR) AF: 0.00 AC: 0 AN: 33638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21600

East Asian (EAS) AF: 0.00 AC: 0 AN: 38342

South Asian (SAS) AF: 0.00 AC: 0 AN: 72966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070306

Other (OTH) AF: 0.0000176 AC: 1 AN: 56796

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 8 Uncertain:1

Feb 08, 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: 470660). 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 glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 953 of the HCN4 protein (p.Gly953Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.41	T
Polyphen		0.42	B
Vest4		0.53
MutPred		0.29		Gain of solvent accessibility (P = 0.0789);
MVP		0.79
MPC		0.23
ClinPred		0.11	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.38
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1555475226; hg19: chr15-73615576;