Genetic Variant HCN1:p.Gly72_Gly74dup (chr5-45695870-T-TCGCCGCCGC) – ACMG Classification: Benign (-10 pts)

Variant summary

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

The NM_021072.4(HCN1):c.215_223dupGCGGCGGCG(p.Gly72_Gly74dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.000288 in 1,563,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

HCN1
NM_021072.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.52

Publications

1 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: Orphanet, ClinGen
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 5-45695870-T-TCGCCGCCGC is Benign according to our data. Variant chr5-45695870-T-TCGCCGCCGC is described in ClinVar as Likely_benign. ClinVar VariationId is 461370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 61 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.215_223dupGCGGCGGCG	p.Gly72_Gly74dup	conservative_inframe_insertion	Exon 1 of 8	NP_066550.2	O60741

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCN1	ENST00000303230.6	TSL:1 MANE Select	c.215_223dupGCGGCGGCG	p.Gly72_Gly74dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000307342.4	O60741
HCN1	ENST00000947598.1		c.215_223dupGCGGCGGCG	p.Gly72_Gly74dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000617657.1
HCN1	ENST00000673735.1		c.215_223dupGCGGCGGCG	p.Gly72_Gly74dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000501107.1	A0A669KB45

Frequencies

GnomAD3 genomes

AF:

0.000412

AC:

AN:

147994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000771

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000267

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000433

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000360

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000608

AC:

AN:

164440

AF XY:

0.0000537

show subpopulations

Gnomad AFR exome

AF:

0.000133

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:

0.0000788

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000276

AC:

390

AN:

1415318

Hom.:

Cov.:

AF XY:

0.000262

AC XY:

184

AN XY:

702516

show subpopulations

African (AFR)

AF:

0.000159

AC:

AN:

31432

American (AMR)

AF:

0.000178

AC:

AN:

39236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24940

East Asian (EAS)

AF:

0.00

AC:

AN:

37864

South Asian (SAS)

AF:

0.000330

AC:

AN:

81850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5298

European-Non Finnish (NFE)

AF:

0.000305

AC:

334

AN:

1095092

Other (OTH)

AF:

0.000291

AC:

AN:

58498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000412

AC:

AN:

148112

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

AN XY:

72348

show subpopulations

African (AFR)

AF:

0.000769

AC:

AN:

40302

American (AMR)

AF:

0.000266

AC:

AN:

15028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4858

South Asian (SAS)

AF:

0.000433

AC:

AN:

4618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.000361

AC:

AN:

66570

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.5

Mutation Taster

=75/25

polymorphism

(source)

Splicing

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

Publications

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5-45695870-TCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

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

Computational scores

Splicing

Publications

Other links and lift over