rs139590882

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005477.3(HCN4):c.1518C>T(p.Tyr506Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,194 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0021 ( 15 hom. )

Consequence

HCN4
NM_005477.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.614

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 15-73329645-G-A is Benign according to our data. Variant chr15-73329645-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.614 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00158 (241/152332) while in subpopulation AMR AF = 0.00183 (28/15314). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 241 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.1518C>T	p.Tyr506Tyr	synonymous	Exon 4 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.1518C>T	p.Tyr506Tyr	synonymous	Exon 4 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00229

AC:

575

AN:

251466

AF XY:

0.00228

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.0252

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00183

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00207

AC:

3028

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1511

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00239

AC:

107

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

686

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00179

AC:

1993

AN:

1111996

Other (OTH)

AF:

0.00344

AC:

208

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

202

404

605

807

1009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00158

AC:

241

AN:

152332

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41584

American (AMR)

AF:

0.00183

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2112

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

Genome Het

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

Alfa

AF:

0.00314

Hom.:

Bravo

AF:

0.00188

EpiCase

AF:

0.00245

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (5)

Brugada syndrome 8 (1)

Cardiovascular phenotype (1)

HCN4-related disorder (1)

Sick sinus syndrome 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.8

(source)

DANN

Benign

0.73

PhyloP100

-0.61

Mutation Taster

=100/0

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