rs749785521
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_005477.3(HCN4):c.3117G>A(p.Pro1039=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 1,413,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00010 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000043 ( 1 hom. )
Consequence
HCN4
NM_005477.3 synonymous
NM_005477.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.02
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 Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
?
Variant 15-73322976-C-T is Benign according to our data. Variant chr15-73322976-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412793.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}.
BP7
?
Synonymous conserved (PhyloP=-1.02 with no splicing effect.
BS2
?
High AC in GnomAd at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.3117G>A | p.Pro1039= | synonymous_variant | 8/8 | ENST00000261917.4 | |
HCN4 | XM_011521148.3 | c.1899G>A | p.Pro633= | synonymous_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.3117G>A | p.Pro1039= | synonymous_variant | 8/8 | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000101 AC: 15AN: 147924Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000459 AC: 29AN: 63138Hom.: 0 AF XY: 0.000360 AC XY: 12AN XY: 33288
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GnomAD4 exome AF: 0.0000435 AC: 55AN: 1265272Hom.: 1 Cov.: 30 AF XY: 0.0000342 AC XY: 21AN XY: 613544
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GnomAD4 genome ? AF: 0.000101 AC: 15AN: 147924Hom.: 0 Cov.: 33 AF XY: 0.000125 AC XY: 9AN XY: 72160
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 13, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2020 | - - |
HCN4-related condition Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 26, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Brugada syndrome 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at