15-73322875-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005477.3(HCN4):​c.3218C>G​(p.Pro1073Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,323,810 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

2
5
12

Clinical Significance

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

Conservation

PhyloP100: 3.11
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33022344).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCN4NM_005477.3 linkc.3218C>G p.Pro1073Arg missense_variant Exon 8 of 8 ENST00000261917.4 NP_005468.1 Q9Y3Q4
HCN4XM_011521148.3 linkc.2000C>G p.Pro667Arg missense_variant Exon 7 of 7 XP_011519450.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HCN4ENST00000261917.4 linkc.3218C>G p.Pro1073Arg missense_variant Exon 8 of 8 1 NM_005477.3 ENSP00000261917.3 Q9Y3Q4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.55e-7
AC:
1
AN:
1323810
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
644806
show subpopulations
Gnomad4 AFR exome
AF:
0.0000331
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brugada syndrome 8 Uncertain:1
Jul 20, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1073 of the HCN4 protein (p.Pro1073Arg). 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. 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. 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. -

Cardiovascular phenotype Uncertain:1
Jan 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P1073R variant (also known as c.3218C>G), located in coding exon 8 of the HCN4 gene, results from a C to G substitution at nucleotide position 3218. The proline at codon 1073 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.074
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.57
T
M_CAP
Pathogenic
0.88
D
MetaRNN
Benign
0.33
T
MetaSVM
Uncertain
0.24
D
MutationAssessor
Benign
1.0
L
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.89
N
REVEL
Benign
0.26
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.010
D
Polyphen
0.0060
B
Vest4
0.38
MutPred
0.27
Gain of MoRF binding (P = 0.0029);
MVP
0.83
MPC
0.73
ClinPred
0.62
D
GERP RS
2.8
Varity_R
0.082
gMVP
0.39

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs982016034; hg19: chr15-73615216; API