Variant 5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BS1_SupportingBS2

The NM_021072.4(HCN1):c.223_224insGCGGCG(p.Gly73_Gly74dup) variant causes a 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 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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 -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021072.4.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000122 (18/148112) while in subpopulation SAS AF= 0.00065 (3/4618). AF 95% confidence interval is 0.000176. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HCN1	ENST00000303230.6 linkuse as main transcript	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/8	1	NM_021072.4	P2
HCN1	ENST00000634658.1 linkuse as main transcript	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/2	3
HCN1	ENST00000673735.1 linkuse as main transcript	c.223_224insGCGGCG	p.Gly73_Gly74dup	inframe_insertion	1/9			A2

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 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 (Invitae). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 17, 2020

- -

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