5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGC

Position:

• chr5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_021072.4(HCN1):​c.218_223del​(p.Gly73_Gly74del) variant causes a 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 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 6.52

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]

ACMG classification

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	UniProt
HCN1	NM_021072.4	c.218_223del	p.Gly73_Gly74del	inframe_deletion	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.218_223del	p.Gly73_Gly74del	inframe_deletion	1/8	1	NM_021072.4	P2
HCN1	ENST00000634658.1	c.218_223del	p.Gly73_Gly74del	inframe_deletion	1/2	3
HCN1	ENST00000673735.1	c.218_223del	p.Gly73_Gly74del	inframe_deletion	1/9			A2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 305 AN: 147994 Hom.: 0 Cov.: 32

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.: 3 AF XY: 0.00369 AC XY: 344 AN XY: 93110

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.: 18 AF XY: 0.00369 AC XY: 2595 AN XY: 702502

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.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 142 AN XY: 72348

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

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HCN1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2016	- -
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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2018	- -

not specified Benign:3

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

Invitae

Jan 27, 2024

- -

HCN1-related disorder Benign:1

Benign, criteria provided, single submitter

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747975797; hg19: chr5-45695972;