rs774400171

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005477.3(HCN4):​c.3575C>T​(p.Pro1192Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,660 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 (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.08
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1181303).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCN4NM_005477.3 linkc.3575C>T p.Pro1192Leu missense_variant Exon 8 of 8 ENST00000261917.4 NP_005468.1 Q9Y3Q4
HCN4XM_011521148.3 linkc.2357C>T p.Pro786Leu 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.3575C>T p.Pro1192Leu missense_variant Exon 8 of 8 1 NM_005477.3 ENSP00000261917.3 Q9Y3Q4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000438
AC:
1
AN:
228244
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
124008
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000988
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1450660
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
720602
show subpopulations
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Brugada syndrome 8 Uncertain:1
Jun 05, 2024
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 leucine, which is neutral and non-polar, at codon 1192 of the HCN4 protein (p.Pro1192Leu). This variant is present in population databases (rs774400171, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 579946). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.0073
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.63
T
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.12
T
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Benign
-0.69
N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.34
Sift
Benign
0.27
T
Sift4G
Uncertain
0.0070
D
Polyphen
0.0
B
Vest4
0.10
MutPred
0.18
Gain of MoRF binding (P = 0.059);
MVP
0.81
MPC
0.39
ClinPred
0.33
T
GERP RS
3.5
Varity_R
0.068
gMVP
0.32

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: rs774400171; hg19: chr15-73614859; API