rs56064803

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_021072.4(HCN1):c.201_209delTGGCGGCGG(p.Gly68_Gly70del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,529,748 control chromosomes in the GnomAD database, including 621 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G67G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 87 hom., cov: 32)

Exomes 𝑓: 0.020 ( 534 hom. )

Consequence

HCN1
NM_021072.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.38

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 24
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
generalized epilepsy with febrile seizures plus
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
generalized epilepsy with febrile seizures plus, type 10
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021072.4.

BP6

Variant 5-45695884-GCCGCCGCCA-G is Benign according to our data. Variant chr5-45695884-GCCGCCGCCA-G is described in ClinVar as Benign. ClinVar VariationId is 95999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000303230.6	NP_066550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HCN1	ENST00000303230.6 link	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4
HCN1	ENST00000673735.1 link	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 9			ENSP00000501107.1
HCN1	ENST00000634658.1 link	c.201_209delTGGCGGCGG	p.Gly68_Gly70del	disruptive_inframe_deletion	Exon 1 of 2	3		ENSP00000489134.1
HCN1	ENST00000638054.1 link	n.-168_-160delTGGCGGCGG		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0284

AC:

4277

AN:

150482

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0621

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000398

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.00774

Gnomad MID

AF:

0.0321

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0222

GnomAD2 exomes

AF:

0.0198

AC:

2842

AN:

143504

AF XY:

0.0205

show subpopulations

Gnomad AFR exome

AF:

0.0798

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.000429

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.0195

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0204

AC:

28203

AN:

1379162

Hom.:

534

AF XY:

0.0205

AC XY:

14004

AN XY:

681950

show subpopulations

African (AFR)

AF:

0.0643

AC:

1981

AN:

30824

American (AMR)

AF:

0.0132

AC:

442

AN:

33594

Ashkenazi Jewish (ASJ)

AF:

0.00156

AC:

AN:

24366

East Asian (EAS)

AF:

0.000165

AC:

AN:

36266

South Asian (SAS)

AF:

0.0289

AC:

2283

AN:

78892

European-Finnish (FIN)

AF:

0.00701

AC:

266

AN:

37968

Middle Eastern (MID)

AF:

0.0288

AC:

147

AN:

5102

European-Non Finnish (NFE)

AF:

0.0203

AC:

21842

AN:

1074886

Other (OTH)

AF:

0.0209

AC:

1198

AN:

57264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1301

2602

3904

5205

6506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0284

AC:

4280

AN:

150586

Hom.:

Cov.:

AF XY:

0.0264

AC XY:

1942

AN XY:

73588

show subpopulations

African (AFR)

AF:

0.0619

AC:

2548

AN:

41156

American (AMR)

AF:

0.0166

AC:

251

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3462

East Asian (EAS)

AF:

0.000399

AC:

AN:

5010

South Asian (SAS)

AF:

0.0216

AC:

103

AN:

4772

European-Finnish (FIN)

AF:

0.00774

AC:

AN:

10332

Middle Eastern (MID)

AF:

0.0313

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0181

AC:

1222

AN:

67402

Other (OTH)

AF:

0.0219

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

196

391

587

782

978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00609

Hom.:

Asia WGS

AF:

0.0110

AC:

AN:

3400

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 08, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 02, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 12, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 13, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=190/10

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over