5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGC

Position:

chr5-45695870-TCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_021072.4(HCN1):c.221_223del(p.Gly74del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

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 -8 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: {Likely_benign=3, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000371 (55/148098) while in subpopulation AFR AF= 0.00127 (51/40300). AF 95% confidence interval is 0.000989. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4 linkuse as main transcript	c.221_223del	p.Gly74del	inframe_deletion	1/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HCN1	ENST00000303230.6 linkuse as main transcript	c.221_223del	p.Gly74del	inframe_deletion	1/8	1	NM_021072.4	P2
HCN1	ENST00000634658.1 linkuse as main transcript	c.221_223del	p.Gly74del	inframe_deletion	1/2	3
HCN1	ENST00000673735.1 linkuse as main transcript	c.221_223del	p.Gly74del	inframe_deletion	1/9			A2

Frequencies

GnomAD3 genomes

AF:

0.000365

AC:

AN:

147980

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00310

AC XY:

289

AN XY:

93110

show subpopulations

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.:

AF XY:

0.000654

AC XY:

453

AN XY:

692868

show subpopulations

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:

AN:

148098

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

AN XY:

72336

show subpopulations

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:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 16, 2023

- -

Developmental and epileptic encephalopathy, 24

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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