5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGC

Variant names:

• chr5-45695870-TCGC-T
• rs747975797
• NM_021072.4:c.221_223delGCG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_021072.4(HCN1):​c.221_223delGCG​(p.Gly74del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000631 in 1,544,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: HCN1 NM_021072.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 Likely_benign. Variant got -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021072.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-45695870-TCGC-T is Benign according to our data. Variant chr5-45695870-TCGC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 581499.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=3}.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4	c.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6	c.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1	c.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1	c.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 2	3		ENSP00000489134.1

Frequencies

GnomAD3 genomes AF: 0.000365 AC: 54 AN: 147980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.000492

GnomAD3 exomes AF: 0.00362 AC: 595 AN: 164440 Hom.: 0 AF XY: 0.00310 AC XY: 289 AN XY: 93110

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00661

Gnomad SAS exome AF: 0.00323

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.000659 AC: 920 AN: 1396448 Hom.: 0 AF XY: 0.000654 AC XY: 453 AN XY: 692868

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00178

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.000372

Gnomad4 OTH exome AF: 0.000956

GnomAD4 genome AF: 0.000371 AC: 55 AN: 148098 Hom.: 0 Cov.: 32 AF XY: 0.000332 AC XY: 24 AN XY: 72336

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.0000666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000300

Gnomad4 OTH AF: 0.000486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 24;C5193120:Generalized epilepsy with febrile seizures plus, type 10 Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HCN1 NM_021072.3 exon 1 p.Gly74del (c.221_223del): This variant has not been reported in the literature and is present in 0.5% (79/13482) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-45695972-TCGC-T). This variant is present in ClinVar (Variation ID:581449). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame deletion of one amino acid at position 74, which is within a repeat region, and it is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Benign:1

Jan 26, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 24 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs747975797; hg19: chr5-45695972;