rs148398509

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005477.3(HCN4):c.2648C>G(p.Pro883Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,609,494 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P883T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0073 ( 6 hom., cov: 33)

Exomes 𝑓: 0.012 ( 143 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 2.86

Publications

15 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

HCN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060073435).

BP6

Variant 15-73323445-G-C is Benign according to our data. Variant chr15-73323445-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00731 (1113/152292) while in subpopulation NFE AF = 0.0115 (782/68008). AF 95% confidence interval is 0.0108. There are 6 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1113 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.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	NM_005477.3	MANE Select	c.2648C>G	p.Pro883Arg	missense	Exon 8 of 8	NP_005468.1	Q9Y3Q4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.2648C>G	p.Pro883Arg	missense	Exon 8 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.00733

AC:

1115

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00724

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.00775

AC:

1837

AN:

236986

AF XY:

0.00746

show subpopulations

Gnomad AFR exome

AF:

0.00219

Gnomad AMR exome

AF:

0.00735

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00798

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.0124

AC:

18106

AN:

1457202

Hom.:

143

Cov.:

AF XY:

0.0120

AC XY:

8671

AN XY:

725088

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33462

American (AMR)

AF:

0.00753

AC:

336

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00280

AC:

AN:

26080

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.00288

AC:

248

AN:

86188

European-Finnish (FIN)

AF:

0.00712

AC:

356

AN:

49994

Middle Eastern (MID)

AF:

0.00401

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0148

AC:

16433

AN:

1111170

Other (OTH)

AF:

0.00957

AC:

577

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

1121

2242

3362

4483

5604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

644

1288

1932

2576

3220

<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:

0.00731

AC:

1113

AN:

152292

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41564

American (AMR)

AF:

0.00712

AC:

109

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00228

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00724

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0115

AC:

782

AN:

68008

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00986

Hom.:

Bravo

AF:

0.00752

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00299

AC:

ESP6500EA

AF:

0.0132

AC:

112

ExAC

AF:

0.00762

AC:

922

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (5)

Brugada syndrome 8 (3)

Sick sinus syndrome 2, autosomal dominant (2)

Atrial fibrillation;C0007194:Hypertrophic cardiomyopathy;C0042514:Ventricular tachycardia;C0878544:Cardiomyopathy (1)

Cardiovascular phenotype (1)

Left ventricular noncompaction (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.18

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

2.9

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.76

REVEL

Benign

0.072

Sift

Uncertain

0.0070

Sift4G

Benign

0.21

Polyphen

0.063

Vest4

0.30

MVP

0.64

MPC

0.19

ClinPred

0.0077

GERP RS

2.6

Varity_R

0.13

gMVP

0.23

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over