rs750833108

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The ENST00000261917.4(HCN4):ā€‹c.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

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.84
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 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
HCN4NM_005477.3 linkuse as main transcriptc.2294C>G p.Ala765Gly missense_variant 8/8 ENST00000261917.4 NP_005468.1
HCN4XM_011521148.3 linkuse as main transcriptc.1076C>G p.Ala359Gly missense_variant 7/7 XP_011519450.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HCN4ENST00000261917.4 linkuse as main transcriptc.2294C>G p.Ala765Gly missense_variant 8/81 NM_005477.3 ENSP00000261917 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
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:
0.0000410
AC:
10
AN:
244114
Hom.:
0
AF XY:
0.0000302
AC XY:
4
AN XY:
132624
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000545
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:
0.00000756
AC:
11
AN:
1454946
Hom.:
0
Cov.:
35
AF XY:
0.00000691
AC XY:
5
AN XY:
724042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingAmbry GeneticsMar 05, 2024The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.36
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.069
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
0.79
D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.059
Sift
Benign
0.049
D
Sift4G
Benign
0.35
T
Polyphen
0.014
B
Vest4
0.061
MutPred
0.35
Loss of helix (P = 0.0033);
MVP
0.44
MPC
0.18
ClinPred
0.091
T
GERP RS
3.2
Varity_R
0.13
gMVP
0.58

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: rs750833108; hg19: chr15-73616140; API