rs982016034

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005477.3(HCN4):​c.3218C>T​(p.Pro1073Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,475,900 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: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.29060838).
BS2
High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCN4NM_005477.3 linkc.3218C>T p.Pro1073Leu missense_variant Exon 8 of 8 ENST00000261917.4 NP_005468.1 Q9Y3Q4
HCN4XM_011521148.3 linkc.2000C>T p.Pro667Leu 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>T p.Pro1073Leu missense_variant Exon 8 of 8 1 NM_005477.3 ENSP00000261917.3 Q9Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152090
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000207
AC:
2
AN:
96392
Hom.:
0
AF XY:
0.0000200
AC XY:
1
AN XY:
50070
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000861
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000232
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000204
AC:
27
AN:
1323810
Hom.:
0
Cov.:
35
AF XY:
0.0000186
AC XY:
12
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:
0.0000529
Gnomad4 SAS exome
AF:
0.0000608
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000172
Gnomad4 OTH exome
AF:
0.0000365
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152090
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000185
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Dec 12, 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 -

Sick sinus syndrome 2, autosomal dominant Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Brugada syndrome 8 Uncertain:1
Jun 30, 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 1073 of the HCN4 protein (p.Pro1073Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 538077). 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. -

Cardiovascular phenotype Uncertain:1
Apr 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P1073L variant (also known as c.3218C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 3218. The proline at codon 1073 is replaced by leucine, an amino acid with similar properties. This amino acid position is well 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
0.093
BayesDel_addAF
Uncertain
0.065
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.58
T
M_CAP
Pathogenic
0.86
D
MetaRNN
Benign
0.29
T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
1.0
L
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.84
N
REVEL
Benign
0.27
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.013
D
Polyphen
0.013
B
Vest4
0.31
MVP
0.85
MPC
0.71
ClinPred
0.60
D
GERP RS
2.8
Varity_R
0.060
gMVP
0.37

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