rs772764704

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005477.3(HCN4):​c.394A>C​(p.Ile132Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,345,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.57
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.089181304).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCN4NM_005477.3 linkc.394A>C p.Ile132Leu missense_variant Exon 1 of 8 ENST00000261917.4 NP_005468.1 Q9Y3Q4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HCN4ENST00000261917.4 linkc.394A>C p.Ile132Leu missense_variant Exon 1 of 8 1 NM_005477.3 ENSP00000261917.3 Q9Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.0000397
AC:
6
AN:
151128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000131
AC:
1
AN:
76208
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
44580
show subpopulations
Gnomad AFR exome
AF:
0.000394
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000502
AC:
6
AN:
1194554
Hom.:
0
Cov.:
31
AF XY:
0.00000687
AC XY:
4
AN XY:
582062
show subpopulations
Gnomad4 AFR exome
AF:
0.0000400
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000372
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000102
Gnomad4 OTH exome
AF:
0.0000628
GnomAD4 genome
AF:
0.0000397
AC:
6
AN:
151128
Hom.:
0
Cov.:
32
AF XY:
0.0000407
AC XY:
3
AN XY:
73786
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
ExAC
AF:
0.00000953
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Jun 27, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 30, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Jun 11, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

HCN4-related disorder Uncertain:1
Jan 20, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HCN4 c.394A>C variant is predicted to result in the amino acid substitution p.Ile132Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-73660218-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Brugada syndrome 8 Uncertain:1
Oct 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 132 of the HCN4 protein (p.Ile132Leu). This variant is present in population databases (rs772764704, gnomAD 0.02%). 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: 538085). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Cardiovascular phenotype Uncertain:1
Dec 23, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.I132L variant (also known as c.394A>C), located in coding exon 1 of the HCN4 gene, results from an A to C substitution at nucleotide position 394. The isoleucine at codon 132 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
22
DANN
Benign
0.94
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.28
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.69
T
M_CAP
Pathogenic
0.89
D
MetaRNN
Benign
0.089
T
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.8
L
PrimateAI
Pathogenic
0.96
D
PROVEAN
Benign
-0.25
N
REVEL
Uncertain
0.30
Sift
Uncertain
0.022
D
Sift4G
Benign
0.16
T
Polyphen
0.20
B
Vest4
0.28
MutPred
0.29
Loss of helix (P = 0.0167);
MVP
0.81
MPC
1.1
ClinPred
0.11
T
GERP RS
1.8
Varity_R
0.19
gMVP
0.23

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: rs772764704; hg19: chr15-73660218; API