rs142735148

Positions:

chr15-73322756-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005477.3(HCN4):c.3337A>G(p.Met1113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,562,790 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 33)

Exomes 𝑓: 0.014 ( 152 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.425

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 (MetaRNN=0.0025372803).

BP6

Variant 15-73322756-T-C is Benign according to our data. Variant chr15-73322756-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 137543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73322756-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0102 (1549/152286) while in subpopulation SAS AF= 0.0207 (100/4826). AF 95% confidence interval is 0.0174. There are 11 homozygotes in gnomad4. There are 691 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1549 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.3337A>G	p.Met1113Val	missense_variant	8/8	ENST00000261917.4	NP_005468.1	Q9Y3Q4
HCN4	XM_011521148.3 linkuse as main transcript	c.2119A>G	p.Met707Val	missense_variant	7/7		XP_011519450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.3337A>G	p.Met1113Val	missense_variant	8/8	1	NM_005477.3	ENSP00000261917.3		Q9Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1548

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00962

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0116

AC:

1855

AN:

159446

Hom.:

AF XY:

0.0125

AC XY:

1074

AN XY:

85932

show subpopulations

Gnomad AFR exome

AF:

0.00758

Gnomad AMR exome

AF:

0.00807

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.0000769

Gnomad SAS exome

AF:

0.0213

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0136

AC:

19193

AN:

1410504

Hom.:

152

Cov.:

AF XY:

0.0140

AC XY:

9740

AN XY:

696756

show subpopulations

Gnomad4 AFR exome

AF:

0.00727

Gnomad4 AMR exome

AF:

0.00864

Gnomad4 ASJ exome

AF:

0.0151

Gnomad4 EAS exome

AF:

0.0000531

Gnomad4 SAS exome

AF:

0.0234

Gnomad4 FIN exome

AF:

0.00252

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.0152

GnomAD4 genome

AF:

0.0102

AC:

1549

AN:

152286

Hom.:

Cov.:

AF XY:

0.00928

AC XY:

691

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00645

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0132

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00669

AC:

ESP6500EA

AF:

0.0126

AC:

107

ExAC

AF:

0.00817

AC:

953

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HCN4: BS1, BS2 -

Sick sinus syndrome 2, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Sep 08, 2017

- -

Sick sinus syndrome 2, autosomal dominant;C2751083:Brugada syndrome 8;C5561983:Epilepsy, idiopathic generalized, susceptibility to, 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 13, 2021

- -

Brugada syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 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

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.18

DANN

Benign

0.36

DEOGEN2

Benign

0.18

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.31

MutationAssessor

Benign

-0.81

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.020

REVEL

Uncertain

0.31

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.042

MPC

0.18

ClinPred

0.000010

GERP RS

-5.1

Varity_R

0.045

gMVP

0.19

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