rs1168642170

Variant names:

• chr15-73367679-C-A
• rs1168642170
• NM_005477.3:c.592G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-73367679-C-A
• chr15-73367679-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005477.3(HCN4):​c.592G>T​(p.Asp198Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. D198E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN4 NM_005477.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3	c.592G>T	p.Asp198Tyr	missense_variant	Exon 1 of 8	ENST00000261917.4	NP_005468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4	c.592G>T	p.Asp198Tyr	missense_variant	Exon 1 of 8	1	NM_005477.3	ENSP00000261917.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1448846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720994

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110820

Other (OTH) AF: 0.00 AC: 0 AN: 60016

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 8 Uncertain:1

May 19, 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. This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 198 of the HCN4 protein (p.Asp198Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.40		Loss of solvent accessibility (P = 0.0193);
MVP		0.91
MPC		1.3
ClinPred		0.83	D
GERP RS		3.7
Varity_R		0.28
gMVP		0.67
Mutation Taster		=67/33	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: rs1168642170; hg19: chr15-73660020;