15-73323114-C-T

Position:

chr15-73323114-C-T

Variant summary

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

The ENST00000261917.4(HCN4):c.2979G>A(p.Thr993=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,593,880 control chromosomes in the GnomAD database, including 40 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. T993T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 21 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 19 hom. )

Consequence

HCN4
ENST00000261917.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.243

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=-0.82).

BP6

Variant 15-73323114-C-T is Benign according to our data. Variant chr15-73323114-C-T is described in ClinVar as [Benign]. Clinvar id is 198827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-73323114-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00906 (1379/152142) while in subpopulation AFR AF= 0.0311 (1292/41498). AF 95% confidence interval is 0.0297. There are 21 homozygotes in gnomad4. There are 670 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1379 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN4	NM_005477.3 linkuse as main transcript	c.2979G>A	p.Thr993=	synonymous_variant	8/8	ENST00000261917.4	NP_005468.1
HCN4	XM_011521148.3 linkuse as main transcript	c.1761G>A	p.Thr587=	synonymous_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.2979G>A	p.Thr993=	synonymous_variant	8/8	1	NM_005477.3	ENSP00000261917	P1

Frequencies

GnomAD3 genomes

AF:

0.00908

AC:

1380

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000776

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00224

AC:

471

AN:

210556

Hom.:

AF XY:

0.00174

AC XY:

203

AN XY:

116740

show subpopulations

Gnomad AFR exome

AF:

0.0322

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000482

Gnomad SAS exome

AF:

0.0000743

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000981

Gnomad OTH exome

AF:

0.000586

GnomAD4 exome

AF:

0.000957

AC:

1380

AN:

1441738

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

615

AN XY:

715656

show subpopulations

Gnomad4 AFR exome

AF:

0.0337

Gnomad4 AMR exome

AF:

0.00189

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000788

Gnomad4 SAS exome

AF:

0.0000963

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000462

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00906

AC:

1379

AN:

152142

Hom.:

Cov.:

AF XY:

0.00901

AC XY:

670

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0311

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000778

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00617

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00144

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	GeneDx	Apr 09, 2015	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)	Aug 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 21, 2022

- -

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 04, 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

-0.82

CADD

Benign

1.9

DANN

Benign

0.34

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