rs140902511

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

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.58
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 -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
HCN4NM_005477.3 linkuse as main transcriptc.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
HCN4ENST00000261917.4 linkuse as main transcriptc.1089C>T p.Ile363= synonymous_variant 2/81 NM_005477.3 ENSP00000261917 P1

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000220
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000115
AC:
29
AN:
251468
Hom.:
0
AF XY:
0.000132
AC XY:
18
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000168
AC:
246
AN:
1461888
Hom.:
1
Cov.:
32
AF XY:
0.000162
AC XY:
118
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000197
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000188
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152312
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000230
Hom.:
0
Bravo
AF:
0.000144
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

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 submitterclinical testingGeneDxJun 24, 2019- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Brugada syndrome 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 23, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2016This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
CADD
Benign
3.0
DANN
Benign
0.88

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: rs140902511; hg19: chr15-73635846; API