dbSNP rs548525: HCN4:c.1210-3238G>C (chr15-73335530-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005477.3(HCN4):c.1210-3238G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.842 in 152,350 control chromosomes in the GnomAD database, including 54,318 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.84 ( 54290 hom., cov: 35)

Exomes 𝑓: 0.83 ( 28 hom. )

Consequence

HCN4
NM_005477.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0170

Publications

3 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: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Brugada syndrome 8
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial sick sinus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

HCN4 links:

ENSG00000259650 (HGNC:58475):

ENSG00000259650 links:

LOC105370890 (HGNC:):

LOC105370890 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HCN4	NM_005477.3 link	c.1210-3238G>C	intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1
LOC105370890	NR_188273.1 link	n.125C>G	non_coding_transcript_exon_variant	Exon 2 of 6
HCN4	XM_011521148.3 link	c.-471G>C	upstream_gene_variant			XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
HCN4	ENST00000261917.4 link	c.1210-3238G>C	intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3
ENSG00000259650	ENST00000557981.1 link	n.109C>G	non_coding_transcript_exon_variant	Exon 2 of 3	2
ENSG00000259650	ENST00000558742.1 link	n.125C>G	non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.842

AC:

128091

AN:

152150

Hom.:

54244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.750

Gnomad AMI

AF:

0.958

Gnomad AMR

AF:

0.909

Gnomad ASJ

AF:

0.878

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.807

Gnomad FIN

AF:

0.824

Gnomad MID

AF:

0.820

Gnomad NFE

AF:

0.887

Gnomad OTH

AF:

0.855

GnomAD4 exome

AF:

0.829

AC:

AN:

Hom.:

Cov.:

AF XY:

0.813

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.800

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.833

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.842

AC:

128194

AN:

152268

Hom.:

54290

Cov.:

AF XY:

0.840

AC XY:

62563

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.750

AC:

31148

AN:

41542

American (AMR)

AF:

0.910

AC:

13927

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

3047

AN:

3472

East Asian (EAS)

AF:

0.806

AC:

4166

AN:

5166

South Asian (SAS)

AF:

0.807

AC:

3898

AN:

4832

European-Finnish (FIN)

AF:

0.824

AC:

8741

AN:

10612

Middle Eastern (MID)

AF:

0.833

AC:

245

AN:

294

European-Non Finnish (NFE)

AF:

0.887

AC:

60342

AN:

68012

Other (OTH)

AF:

0.853

AC:

1806

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1070

2139

3209

4278

5348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.863

Hom.:

6237

Bravo

AF:

0.846

Asia WGS

AF:

0.793

AC:

2759

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.9

(source)

DANN

Benign

0.55

PhyloP100

0.017

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over