chr15-73322587-CCAAA-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_005477.3(HCN4):​c.3502_3505delTTTG​(p.Phe1168GlyfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.000112 in 1,610,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

HCN4
NM_005477.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 5.59

Publications

1 publications found
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]
HCN4 Gene-Disease associations (from GenCC):
  • sick sinus syndrome 2, autosomal dominant
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • Brugada syndrome 8
    Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • familial sick sinus syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Brugada syndrome 1
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0305 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS2
High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005477.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HCN4
NM_005477.3
MANE Select
c.3502_3505delTTTGp.Phe1168GlyfsTer12
frameshift
Exon 8 of 8NP_005468.1Q9Y3Q4

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HCN4
ENST00000261917.4
TSL:1 MANE Select
c.3502_3505delTTTGp.Phe1168GlyfsTer12
frameshift
Exon 8 of 8ENSP00000261917.3Q9Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152144
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000108
AC:
26
AN:
240632
AF XY:
0.0000841
show subpopulations
Gnomad AFR exome
AF:
0.000132
Gnomad AMR exome
AF:
0.000147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000166
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000121
Gnomad OTH exome
AF:
0.000170
GnomAD4 exome
AF:
0.000104
AC:
152
AN:
1458350
Hom.:
0
AF XY:
0.0000883
AC XY:
64
AN XY:
725078
show subpopulations
African (AFR)
AF:
0.000120
AC:
4
AN:
33436
American (AMR)
AF:
0.000225
AC:
10
AN:
44362
Ashkenazi Jewish (ASJ)
AF:
0.0000767
AC:
2
AN:
26066
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39600
South Asian (SAS)
AF:
0.000117
AC:
10
AN:
85528
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.000104
AC:
115
AN:
1110776
Other (OTH)
AF:
0.000183
AC:
11
AN:
60222
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.459
Heterozygous variant carriers
0
9
17
26
34
43
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152144
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74288
show subpopulations
African (AFR)
AF:
0.000362
AC:
15
AN:
41440
American (AMR)
AF:
0.000196
AC:
3
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5144
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000132
AC:
9
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000155

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
6
-
not provided (6)
-
1
-
Brugada syndrome 8 (1)
-
1
-
Cardiovascular phenotype (1)
-
1
-
Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18 (1)
-
1
-
Sinoatrial node disorder (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
5.6
Mutation Taster
=56/144
disease causing

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

Other links and lift over

dbSNP: rs786205259; hg19: chr15-73614928; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.