Variant 15-73320492-C-T 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.*1989G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,198 control chromosomes in the GnomAD database, including 52,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 51998 hom., cov: 31)

Exomes 𝑓: 0.87 ( 24 hom. )

Consequence

HCN4
NM_005477.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.40

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=-0.98).

BP6

Variant 15-73320492-C-T is Benign according to our data. Variant chr15-73320492-C-T is described in ClinVar as [Benign]. Clinvar id is 886590.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	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.*1989G>A		3_prime_UTR_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3 linkuse as main transcript	c.*1989G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.*1989G>A		3_prime_UTR_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes

AF:

0.807

AC:

122685

AN:

152018

Hom.:

51986

Cov.:

show subpopulations

Gnomad AFR

AF:

0.520

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.910

Gnomad ASJ

AF:

0.878

Gnomad EAS

AF:

0.813

Gnomad SAS

AF:

0.822

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.932

Gnomad OTH

AF:

0.832

GnomAD4 exome

AF:

0.871

AC:

AN:

Hom.:

Cov.:

AF XY:

0.854

AC XY:

AN XY:

show subpopulations

Gnomad4 AFR exome

AF:

0.500

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

0.957

Gnomad4 OTH exome

AF:

0.833

GnomAD4 genome

AF:

0.807

AC:

122733

AN:

152136

Hom.:

51998

Cov.:

AF XY:

0.810

AC XY:

60278

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.519

Gnomad4 AMR

AF:

0.911

Gnomad4 ASJ

AF:

0.878

Gnomad4 EAS

AF:

0.813

Gnomad4 SAS

AF:

0.822

Gnomad4 FIN

AF:

0.928

Gnomad4 NFE

AF:

0.932

Gnomad4 OTH

AF:

0.827

Alfa

AF:

0.900

Hom.:

45620

Bravo

AF:

0.795

Asia WGS

AF:

0.767

AC:

2666

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sick sinus syndrome 2, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.12

DANN

Benign

0.45

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

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