Variant chr5-45695870-T-TCGCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_021072.4(HCN1):c.218_223dupGCGGCG(p.Gly73_Gly74dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.000108 in 1,563,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

HCN1
NM_021072.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

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 Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021072.4.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.218_223dupGCGGCG	p.Gly73_Gly74dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000303230.6	NP_066550.2	O60741Q86WJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCN1	ENST00000303230.6 link	c.218_223dupGCGGCG	p.Gly73_Gly74dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 link	c.218_223dupGCGGCG	p.Gly73_Gly74dup	conservative_inframe_insertion	Exon 1 of 9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000634658.1 link	c.218_223dupGCGGCG	p.Gly73_Gly74dup	conservative_inframe_insertion	Exon 1 of 2	3		ENSP00000489134.1	A0A0U1RQR7

Frequencies

GnomAD3 genomes

AF:

0.000122

AC:

AN:

147994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000333

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000205

Gnomad SAS

AF:

0.000650

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000105

Gnomad OTH

AF:

0.000492

GnomAD4 exome

AF:

0.000107

AC:

151

AN:

1415348

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

702536

show subpopulations

Gnomad4 AFR exome

AF:

0.0000636

Gnomad4 AMR exome

AF:

0.0000765

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000185

Gnomad4 SAS exome

AF:

0.000195

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000986

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000122

AC:

AN:

148112

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72348

show subpopulations

Gnomad4 AFR

AF:

0.0000248

Gnomad4 AMR

AF:

0.000333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000206

Gnomad4 SAS

AF:

0.000650

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000105

Gnomad4 OTH

AF:

0.000486

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2023	In-frame duplication of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2020	- -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2024

This variant, c.218_223dup, results in the insertion of 2 amino acid(s) of the HCN1 protein (p.Gly73_Gly74dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCN1-related conditions. This variant has been observed in at least one individual who was not affected with HCN1-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 647637). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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