Genetic Variant NM_005477.3:c.1210-1806G>A (chr15-73334098-C-T) – 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.1210-1806G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,150 control chromosomes in the GnomAD database, including 7,918 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 0.30 ( 7918 hom., cov: 32)

Consequence

HCN4
NM_005477.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.715

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: 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:

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=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN4	NM_005477.3 link	c.1210-1806G>A		intron_variant	Intron 2 of 7	ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 link	c.-10+971G>A		intron_variant	Intron 1 of 6		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 link	c.1210-1806G>A		intron_variant	Intron 2 of 7	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45607

AN:

152030

Hom.:

7923

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.429

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.449

Gnomad EAS

AF:

0.541

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.324

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.300

AC:

45602

AN:

152150

Hom.:

7918

Cov.:

AF XY:

0.302

AC XY:

22441

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.112

AC:

4655

AN:

41534

American (AMR)

AF:

0.341

AC:

5216

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

1557

AN:

3466

East Asian (EAS)

AF:

0.541

AC:

2786

AN:

5152

South Asian (SAS)

AF:

0.377

AC:

1817

AN:

4818

European-Finnish (FIN)

AF:

0.333

AC:

3523

AN:

10590

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.366

AC:

24866

AN:

67986

Other (OTH)

AF:

0.324

AC:

684

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1584

3168

4751

6335

7919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.235

Hom.:

796

Bravo

AF:

0.294

Asia WGS

AF:

0.389

AC:

1351

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.90

(source)

DANN

Benign

0.80

PhyloP100

-0.71

Mutation Taster

=100/0

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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NM_005477.3:c.1210-1806G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over