5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGC

Position:

chr5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_021072.4(HCN1):c.215_223del(p.Gly72_Gly74del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00245 in 1,563,448 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G72G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 15 hom. )

Consequence

HCN1
NM_021072.4 inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 6.52

Variant links:

Genes affected

HCN1 (HGNC:4845): (hyperpolarization activated cyclic nucleotide gated potassium channel 1) The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

HCN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021072.4.

BP6

Variant 5-45695870-TCGCCGCCGC-T is Benign according to our data. Variant chr5-45695870-TCGCCGCCGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 193441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-45695870-TCGCCGCCGC-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00198 (293/148110) while in subpopulation NFE AF= 0.00276 (184/66570). AF 95% confidence interval is 0.00244. There are 2 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 293 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.215_223del	p.Gly72_Gly74del	inframe_deletion	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HCN1	ENST00000303230.6 linkuse as main transcript	c.215_223del	p.Gly72_Gly74del	inframe_deletion	1/8	1	NM_021072.4	P2
HCN1	ENST00000634658.1 linkuse as main transcript	c.215_223del	p.Gly72_Gly74del	inframe_deletion	1/2	3
HCN1	ENST00000673735.1 linkuse as main transcript	c.215_223del	p.Gly72_Gly74del	inframe_deletion	1/9			A2

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

293

AN:

147992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00253

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000616

Gnomad SAS

AF:

0.000217

Gnomad FIN

AF:

0.000198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.00246

GnomAD3 exomes

AF:

0.00193

AC:

317

AN:

164440

Hom.:

AF XY:

0.00189

AC XY:

176

AN XY:

93110

show subpopulations

Gnomad AFR exome

AF:

0.00147

Gnomad AMR exome

AF:

0.00308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.000398

Gnomad FIN exome

AF:

0.0000857

Gnomad NFE exome

AF:

0.00284

Gnomad OTH exome

AF:

0.00173

GnomAD4 exome

AF:

0.00250

AC:

3542

AN:

1415338

Hom.:

AF XY:

0.00238

AC XY:

1672

AN XY:

702538

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000238

Gnomad4 SAS exome

AF:

0.000379

Gnomad4 FIN exome

AF:

0.000146

Gnomad4 NFE exome

AF:

0.00295

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00198

AC:

293

AN:

148110

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

142

AN XY:

72348

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00253

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000618

Gnomad4 SAS

AF:

0.000217

Gnomad4 FIN

AF:

0.000198

Gnomad4 NFE

AF:

0.00276

Gnomad4 OTH

AF:

0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	This variant is associated with the following publications: (PMID: 17931874) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HCN1: BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 26, 2014

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2018

This alteration is classified as likely 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. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Developmental and epileptic encephalopathy, 24

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

HCN1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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