chr5-45695870-TCGC-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS2

The NM_021072.4(HCN1):c.221_223delGCG(p.Gly74del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

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: Likely_benign. The variant received -4 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 VariationId is 581499.

BS2

High AC in GnomAd4 at 55 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.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	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.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000307342.4	O60741
HCN1	ENST00000947598.1		c.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000617657.1
HCN1	ENST00000673735.1		c.221_223delGCG	p.Gly74del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000501107.1	A0A669KB45

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

GnomAD2 exomes

AF:

0.00362

AC:

595

AN:

164440

AF XY:

0.00310

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00294

AC:

AN:

30966

American (AMR)

AF:

0.00407

AC:

154

AN:

37802

Ashkenazi Jewish (ASJ)

AF:

0.00139

AC:

AN:

24406

East Asian (EAS)

AF:

0.00178

AC:

AN:

37004

South Asian (SAS)

AF:

0.00112

AC:

AN:

79138

European-Finnish (FIN)

AF:

0.000568

AC:

AN:

40468

Middle Eastern (MID)

AF:

0.000953

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.000372

AC:

403

AN:

1083876

Other (OTH)

AF:

0.000956

AC:

AN:

57544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.271

Heterozygous variant carriers

132

265

397

530

662

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:

0.000371

AC:

AN:

148098

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

AN XY:

72336

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

40300

American (AMR)

AF:

0.0000666

AC:

AN:

15026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4858

South Asian (SAS)

AF:

0.00

AC:

AN:

4618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66564

Other (OTH)

AF:

0.000486

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.00703

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

Developmental and epileptic encephalopathy, 24 (1)

Developmental and epileptic encephalopathy, 24;C5193120:Generalized epilepsy with febrile seizures plus, type 10 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.5

Mutation Taster

=79/21

polymorphism

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over