rs147181577

Positions:

chr15-73322506-C-T

Variant summary

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

The NM_005477.3(HCN4):c.3587G>A(p.Arg1196His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,599,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1196C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

HCN4
NM_005477.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.79

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=0.008200079).

BP6

Variant 15-73322506-C-T is Benign according to our data. Variant chr15-73322506-C-T is described in ClinVar as [Benign]. Clinvar id is 198820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73322506-C-T is described in Lovd as [Benign]. Variant chr15-73322506-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000263 (380/1446756) while in subpopulation AFR AF= 0.00772 (256/33162). AF 95% confidence interval is 0.00694. There are 0 homozygotes in gnomad4_exome. There are 145 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.

BS2

High AC in GnomAd4 at 280 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.3587G>A	p.Arg1196His	missense_variant	8/8	ENST00000261917.4
HCN4	XM_011521148.3 linkuse as main transcript	c.2369G>A	p.Arg790His	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN4	ENST00000261917.4 linkuse as main transcript	c.3587G>A	p.Arg1196His	missense_variant	8/8	1	NM_005477.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00611

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000512

AC:

114

AN:

222718

Hom.:

AF XY:

0.000356

AC XY:

AN XY:

120912

show subpopulations

Gnomad AFR exome

AF:

0.00676

Gnomad AMR exome

AF:

0.000187

Gnomad ASJ exome

AF:

0.00117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000408

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000263

AC:

380

AN:

1446756

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

145

AN XY:

718332

show subpopulations

Gnomad4 AFR exome

AF:

0.00772

Gnomad4 AMR exome

AF:

0.000234

Gnomad4 ASJ exome

AF:

0.00178

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000335

Gnomad4 OTH exome

AF:

0.000485

GnomAD4 genome

AF:

0.00184

AC:

280

AN:

152280

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00614

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000441

Hom.:

Bravo

AF:

0.00209

ESP6500AA

AF:

0.00570

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000479

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2016	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 provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Brugada syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2019

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

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0082

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.73

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.24

MVP

0.92

MPC

0.27

ClinPred

0.040

GERP RS

3.5

Varity_R

0.16

gMVP

0.36

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