5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGC

Position:

chr5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGC

Variant summary

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

The NM_021072.4(HCN1):c.218_223delGCGGCG(p.Gly73_Gly74del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00344 in 1,563,414 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 18 hom. )

Consequence

HCN1
NM_021072.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

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-TCGCCGC-T is Benign according to our data. Variant chr5-45695870-TCGCCGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 241373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-45695870-TCGCCGC-T is described in Lovd as [Likely_benign]. Variant chr5-45695870-TCGCCGC-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00206 (305/148112) while in subpopulation SAS AF= 0.00606 (28/4618). AF 95% confidence interval is 0.00431. There are 0 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 305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	1/8	ENST00000303230.6	NP_066550.2	O60741Q86WJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HCN1	ENST00000303230.6 linkuse as main transcript	c.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	1/8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 linkuse as main transcript	c.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	1/9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000634658.1 linkuse as main transcript	c.218_223delGCGGCG	p.Gly73_Gly74del	disruptive_inframe_deletion	1/2	3		ENSP00000489134.1	A0A0U1RQR7

Frequencies

GnomAD3 genomes

AF:

0.00206

AC:

305

AN:

147994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000373

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000933

Gnomad ASJ

AF:

0.000292

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00606

Gnomad FIN

AF:

0.000297

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.00442

GnomAD3 exomes

AF:

0.00343

AC:

564

AN:

164440

Hom.:

AF XY:

0.00369

AC XY:

344

AN XY:

93110

show subpopulations

Gnomad AFR exome

AF:

0.000400

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00885

Gnomad FIN exome

AF:

0.000343

Gnomad NFE exome

AF:

0.00393

Gnomad OTH exome

AF:

0.00296

GnomAD4 exome

AF:

0.00359

AC:

5076

AN:

1415302

Hom.:

AF XY:

0.00369

AC XY:

2595

AN XY:

702502

show subpopulations

Gnomad4 AFR exome

AF:

0.000636

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.000481

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00728

Gnomad4 FIN exome

AF:

0.000633

Gnomad4 NFE exome

AF:

0.00385

Gnomad4 OTH exome

AF:

0.00255

GnomAD4 genome

AF:

0.00206

AC:

305

AN:

148112

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

142

AN XY:

72348

show subpopulations

Gnomad4 AFR

AF:

0.000372

Gnomad4 AMR

AF:

0.000932

Gnomad4 ASJ

AF:

0.000292

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00606

Gnomad4 FIN

AF:

0.000297

Gnomad4 NFE

AF:

0.00353

Gnomad4 OTH

AF:

0.00437

Bravo

AF:

0.00210

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	GeneDx	Nov 12, 2020	Identified using alternate nomenclature p.73_75del in a patient with epilepsy, however, this individual had variants in other genes that may have contributed to their phenotype (Friedman et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In-frame deletion in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 29619247) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	HCN1: BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 09, 2021	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

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. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

HCN1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as 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