NM_021072.4:c.201_209dupTGGCGGCGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4BP6_Very_StrongBS2

The NM_021072.4(HCN1):c.201_209dupTGGCGGCGG(p.Gly68_Gly70dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,529,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G70G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

HCN1
NM_021072.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

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 -10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021072.4.

BP6

Variant 5-45695884-G-GCCGCCGCCA is Benign according to our data. Variant chr5-45695884-G-GCCGCCGCCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021072.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.201_209dupTGGCGGCGG	p.Gly68_Gly70dup	disruptive_inframe_insertion	Exon 1 of 8	NP_066550.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCN1	ENST00000303230.6	TSL:1 MANE Select	c.201_209dupTGGCGGCGG	p.Gly68_Gly70dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000307342.4
HCN1	ENST00000673735.1		c.201_209dupTGGCGGCGG	p.Gly68_Gly70dup	disruptive_inframe_insertion	Exon 1 of 9	ENSP00000501107.1
HCN1	ENST00000634658.1	TSL:3	c.201_209dupTGGCGGCGG	p.Gly68_Gly70dup	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000489134.1

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

150518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000968

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000237

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

143504

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

223

AN:

1379162

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

114

AN XY:

681952

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30826

American (AMR)

AF:

0.0000298

AC:

AN:

33594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24366

East Asian (EAS)

AF:

0.0000276

AC:

AN:

36266

South Asian (SAS)

AF:

0.0000761

AC:

AN:

78888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5102

European-Non Finnish (NFE)

AF:

0.000195

AC:

210

AN:

1074890

Other (OTH)

AF:

0.0000699

AC:

AN:

57262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000179

AC:

AN:

150622

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73604

show subpopulations

African (AFR)

AF:

0.000194

AC:

AN:

41178

American (AMR)

AF:

0.000132

AC:

AN:

15162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5010

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.0000968

AC:

AN:

10332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000237

AC:

AN:

67410

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Jun 14, 2022

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=72/28

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over