15-73323537-C-T

Position:

chr15-73323537-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005477.3(HCN4):c.2556G>A(p.Pro852=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,601,002 control chromosomes in the GnomAD database, including 1,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P852P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.037 ( 150 hom., cov: 33)

Exomes 𝑓: 0.046 ( 1839 hom. )

Consequence

HCN4
NM_005477.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.21

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 15-73323537-C-T is Benign according to our data. Variant chr15-73323537-C-T is described in ClinVar as [Benign]. Clinvar id is 95284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73323537-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0726 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.2556G>A	p.Pro852=	synonymous_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3 linkuse as main transcript	c.1338G>A	p.Pro446=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.2556G>A	p.Pro852=	synonymous_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5651

AN:

152160

Hom.:

148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0758

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0501

Gnomad OTH

AF:

0.0493

GnomAD3 exomes

AF:

0.0489

AC:

11512

AN:

235532

Hom.:

395

AF XY:

0.0476

AC XY:

6113

AN XY:

128470

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.0457

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0501

Gnomad OTH exome

AF:

0.0536

GnomAD4 exome

AF:

0.0461

AC:

66785

AN:

1448724

Hom.:

1839

Cov.:

AF XY:

0.0460

AC XY:

33153

AN XY:

721108

show subpopulations

Gnomad4 AFR exome

AF:

0.00839

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.0220

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0471

Gnomad4 FIN exome

AF:

0.0236

Gnomad4 NFE exome

AF:

0.0481

Gnomad4 OTH exome

AF:

0.0421

GnomAD4 genome

AF:

0.0372

AC:

5661

AN:

152278

Hom.:

150

Cov.:

AF XY:

0.0366

AC XY:

2727

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0112

Gnomad4 AMR

AF:

0.0763

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0468

Gnomad4 FIN

AF:

0.0194

Gnomad4 NFE

AF:

0.0501

Gnomad4 OTH

AF:

0.0488

Alfa

AF:

0.0221

Hom.:

Bravo

AF:

0.0402

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0518

EpiControl

AF:

0.0529

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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. -

Brugada syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.4

DANN

Benign

0.60

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