NM_005477.3:c.107G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005477.3(HCN4):c.107G>A(p.Gly36Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,528,838 control chromosomes in the GnomAD database, including 2,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. G36R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.045 ( 219 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2693 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.04

Publications

12 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=0.0012548864).

BP6

Variant 15-73368164-C-T is Benign according to our data. Variant chr15-73368164-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

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.107G>A	p.Gly36Glu	missense	Exon 1 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.107G>A	p.Gly36Glu	missense	Exon 1 of 8	ENSP00000261917.3	Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0446

AC:

6765

AN:

151844

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0588

Gnomad ASJ

AF:

0.0917

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.0796

Gnomad NFE

AF:

0.0666

Gnomad OTH

AF:

0.0752

GnomAD2 exomes

AF:

0.0473

AC:

5972

AN:

126370

AF XY:

0.0473

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0461

Gnomad ASJ exome

AF:

0.0945

Gnomad EAS exome

AF:

0.000459

Gnomad FIN exome

AF:

0.0296

Gnomad NFE exome

AF:

0.0650

Gnomad OTH exome

AF:

0.0725

GnomAD4 exome

AF:

0.0586

AC:

80663

AN:

1376886

Hom.:

2693

Cov.:

AF XY:

0.0578

AC XY:

39306

AN XY:

680050

show subpopulations

African (AFR)

AF:

0.0112

AC:

319

AN:

28588

American (AMR)

AF:

0.0474

AC:

1656

AN:

34966

Ashkenazi Jewish (ASJ)

AF:

0.0952

AC:

2324

AN:

24406

East Asian (EAS)

AF:

0.000300

AC:

AN:

33292

South Asian (SAS)

AF:

0.0244

AC:

1889

AN:

77522

European-Finnish (FIN)

AF:

0.0289

AC:

1275

AN:

44192

Middle Eastern (MID)

AF:

0.0999

AC:

534

AN:

5346

European-Non Finnish (NFE)

AF:

0.0645

AC:

69138

AN:

1071472

Other (OTH)

AF:

0.0616

AC:

3518

AN:

57102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

4153

8306

12458

16611

20764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2564

5128

7692

10256

12820

<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:

0.0445

AC:

6765

AN:

151952

Hom.:

219

Cov.:

AF XY:

0.0430

AC XY:

3192

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0114

AC:

475

AN:

41522

American (AMR)

AF:

0.0587

AC:

897

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0917

AC:

318

AN:

3468

East Asian (EAS)

AF:

0.000195

AC:

AN:

5122

South Asian (SAS)

AF:

0.0226

AC:

109

AN:

4832

European-Finnish (FIN)

AF:

0.0239

AC:

252

AN:

10530

Middle Eastern (MID)

AF:

0.0890

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0666

AC:

4519

AN:

67886

Other (OTH)

AF:

0.0744

AC:

157

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

341

682

1024

1365

1706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0604

Hom.:

134

Bravo

AF:

0.0458

TwinsUK

AF:

0.0636

AC:

236

ALSPAC

AF:

0.0599

AC:

231

ESP6500AA

AF:

0.00768

AC:

ESP6500EA

AF:

0.0508

AC:

378

ExAC

AF:

0.0222

AC:

2327

Asia WGS

AF:

0.0130

AC:

AN:

3382

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (2)

Brugada syndrome 8 (1)

Cardiovascular phenotype (1)

Sick sinus syndrome 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.55

PhyloP100

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.67

REVEL

Benign

0.23

Sift

Uncertain

0.0020

Sift4G

Benign

0.096

Polyphen

0.0040

Vest4

0.085

MPC

1.4

ClinPred

0.0047

GERP RS

2.0

Varity_R

0.21

gMVP

0.25

Mutation Taster

=91/9

polymorphism (auto)

(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