rs143090627

Positions:

chr15-73368164-C-T

Variant summary

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

The NM_005477.3(HCN4):c.107G>A(p.Gly36Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,528,838 control chromosomes in the GnomAD database, including 2,912 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G36R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.045 ( 219 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2693 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.04

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=0.0012548864).

BP6

Variant 15-73368164-C-T is Benign according to our data. Variant chr15-73368164-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73368164-C-T is described in Lovd as [Benign]. Variant chr15-73368164-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 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.107G>A	p.Gly36Glu	missense_variant	1/8	ENST00000261917.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.107G>A	p.Gly36Glu	missense_variant	1/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0446

AC:

6765

AN:

151844

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0588

Gnomad ASJ

AF:

0.0917

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.0796

Gnomad NFE

AF:

0.0666

Gnomad OTH

AF:

0.0752

GnomAD3 exomes

AF:

0.0473

AC:

5972

AN:

126370

Hom.:

222

AF XY:

0.0473

AC XY:

3309

AN XY:

70004

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0461

Gnomad ASJ exome

AF:

0.0945

Gnomad EAS exome

AF:

0.000459

Gnomad SAS exome

AF:

0.0236

Gnomad FIN exome

AF:

0.0296

Gnomad NFE exome

AF:

0.0650

Gnomad OTH exome

AF:

0.0725

GnomAD4 exome

AF:

0.0586

AC:

80663

AN:

1376886

Hom.:

2693

Cov.:

AF XY:

0.0578

AC XY:

39306

AN XY:

680050

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.0474

Gnomad4 ASJ exome

AF:

0.0952

Gnomad4 EAS exome

AF:

0.000300

Gnomad4 SAS exome

AF:

0.0244

Gnomad4 FIN exome

AF:

0.0289

Gnomad4 NFE exome

AF:

0.0645

Gnomad4 OTH exome

AF:

0.0616

GnomAD4 genome

AF:

0.0445

AC:

6765

AN:

151952

Hom.:

219

Cov.:

AF XY:

0.0430

AC XY:

3192

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0114

Gnomad4 AMR

AF:

0.0587

Gnomad4 ASJ

AF:

0.0917

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.0226

Gnomad4 FIN

AF:

0.0239

Gnomad4 NFE

AF:

0.0666

Gnomad4 OTH

AF:

0.0744

Alfa

AF:

0.0604

Hom.:

134

Bravo

AF:

0.0458

TwinsUK

AF:

0.0636

AC:

236

ALSPAC

AF:

0.0599

AC:

231

ESP6500AA

AF:

0.00768

AC:

ESP6500EA

AF:

0.0508

AC:

378

ExAC

AF:

0.0222

AC:

2327

Asia WGS

AF:

0.0130

AC:

AN:

3382

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

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	May 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Sick sinus syndrome 2, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 18, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

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

Aug 01, 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

0.083

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.67

REVEL

Benign

0.23

Sift

Uncertain

0.0020

Sift4G

Benign

0.096

Polyphen

0.0040

Vest4

0.085

MPC

1.4

ClinPred

0.0047

GERP RS

2.0

Varity_R

0.21

gMVP

0.25

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