rs140902511
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_005477.3(HCN4):c.1089C>T(p.Ile363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,614,200 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 1 hom. )
Consequence
HCN4
NM_005477.3 synonymous
NM_005477.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.58
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 -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 15-73343505-G-A is Benign according to our data. Variant chr15-73343505-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 412787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73343505-G-A is described in Lovd as [Benign]. Variant chr15-73343505-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-1.58 with no splicing effect.
BS2
High AC in GnomAd4 at 24 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.1089C>T | p.Ile363= | synonymous_variant | 2/8 | ENST00000261917.4 | NP_005468.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.1089C>T | p.Ile363= | synonymous_variant | 2/8 | 1 | NM_005477.3 | ENSP00000261917 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251468Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135916
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GnomAD4 exome AF: 0.000168 AC: 246AN: 1461888Hom.: 1 Cov.: 32 AF XY: 0.000162 AC XY: 118AN XY: 727246
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GnomAD4 genome AF: 0.000158 AC: 24AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74486
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Brugada syndrome 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2016 | 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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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