rs750833108
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The ENST00000261917.4(HCN4):āc.2294C>Gā(p.Ala765Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000871 in 1,607,146 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.0000076 ( 0 hom. )
Consequence
HCN4
ENST00000261917.4 missense
ENST00000261917.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 3.84
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 -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.06947234).
BP6
Variant 15-73323799-G-C is Benign according to our data. Variant chr15-73323799-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404137.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAdExome4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.2294C>G | p.Ala765Gly | missense_variant | 8/8 | ENST00000261917.4 | NP_005468.1 | |
HCN4 | XM_011521148.3 | c.1076C>G | p.Ala359Gly | missense_variant | 7/7 | XP_011519450.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.2294C>G | p.Ala765Gly | missense_variant | 8/8 | 1 | NM_005477.3 | ENSP00000261917 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000410 AC: 10AN: 244114Hom.: 0 AF XY: 0.0000302 AC XY: 4AN XY: 132624
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GnomAD4 exome AF: 0.00000756 AC: 11AN: 1454946Hom.: 0 Cov.: 35 AF XY: 0.00000691 AC XY: 5AN XY: 724042
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2024 | The c.2294C>G (p.A765G) alteration is located in exon 8 (coding exon 8) of the HCN4 gene. This alteration results from a C to G substitution at nucleotide position 2294, causing the alanine (A) at amino acid position 765 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Brugada syndrome 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of helix (P = 0.0033);
MVP
MPC
ClinPred
T
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gMVP
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