Variant chr15-73324294-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005477.3(HCN4):c.1979-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,607,054 control chromosomes in the GnomAD database, including 664,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 52669 hom., cov: 34)

Exomes 𝑓: 0.91 ( 611679 hom. )

Consequence

HCN4
NM_005477.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0590

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 15-73324294-T-C is Benign according to our data. Variant chr15-73324294-T-C is described in ClinVar as [Benign]. Clinvar id is 259779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.1979-41A>G		intron_variant		ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 linkuse as main transcript	c.761-41A>G		intron_variant			XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.1979-41A>G		intron_variant		1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.814

AC:

123857

AN:

152108

Hom.:

52656

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.912

Gnomad ASJ

AF:

0.879

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.829

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.861

Gnomad NFE

AF:

0.932

Gnomad OTH

AF:

0.838

GnomAD3 exomes

AF:

0.885

AC:

210391

AN:

237842

Hom.:

94197

AF XY:

0.888

AC XY:

114778

AN XY:

129320

show subpopulations

Gnomad AFR exome

AF:

0.535

Gnomad AMR exome

AF:

0.948

Gnomad ASJ exome

AF:

0.873

Gnomad EAS exome

AF:

0.826

Gnomad SAS exome

AF:

0.837

Gnomad FIN exome

AF:

0.926

Gnomad NFE exome

AF:

0.929

Gnomad OTH exome

AF:

0.902

GnomAD4 exome

AF:

0.914

AC:

1330440

AN:

1454828

Hom.:

611679

Cov.:

AF XY:

0.913

AC XY:

660167

AN XY:

723454

show subpopulations

Gnomad4 AFR exome

AF:

0.530

Gnomad4 AMR exome

AF:

0.943

Gnomad4 ASJ exome

AF:

0.876

Gnomad4 EAS exome

AF:

0.838

Gnomad4 SAS exome

AF:

0.834

Gnomad4 FIN exome

AF:

0.928

Gnomad4 NFE exome

AF:

0.936

Gnomad4 OTH exome

AF:

0.889

GnomAD4 genome

AF:

0.814

AC:

123907

AN:

152226

Hom.:

52669

Cov.:

AF XY:

0.817

AC XY:

60848

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.543

Gnomad4 AMR

AF:

0.913

Gnomad4 ASJ

AF:

0.879

Gnomad4 EAS

AF:

0.817

Gnomad4 SAS

AF:

0.829

Gnomad4 FIN

AF:

0.928

Gnomad4 NFE

AF:

0.932

Gnomad4 OTH

AF:

0.833

Alfa

AF:

0.876

Hom.:

10988

Bravo

AF:

0.803

Asia WGS

AF:

0.775

AC:

2697

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.55

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over