chr5-45695954-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_021072.4(HCN1):c.140G>T(p.Gly47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,332,860 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G47R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 26 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.91

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005699843).

BP6

Variant 5-45695954-C-A is Benign according to our data. Variant chr5-45695954-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 523 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.140G>T	p.Gly47Val	missense_variant	Exon 1 of 8	ENST00000303230.6	NP_066550.2	O60741Q86WJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCN1	ENST00000303230.6 link	c.140G>T	p.Gly47Val	missense_variant	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 link	c.140G>T	p.Gly47Val	missense_variant	Exon 1 of 9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000634658.1 link	c.140G>T	p.Gly47Val	missense_variant	Exon 1 of 2	3		ENSP00000489134.1	A0A0U1RQR7
HCN1	ENST00000638054.1 link	n.-229G>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

523

AN:

149810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00252

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.00213

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.00612

Gnomad OTH

AF:

0.00388

GnomAD2 exomes

AF:

0.00661

AC:

143

AN:

21648

AF XY:

0.00673

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00247

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00451

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.00383

GnomAD4 exome

AF:

0.00620

AC:

7333

AN:

1182940

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

3540

AN XY:

577248

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

23052

American (AMR)

AF:

0.00206

AC:

AN:

10186

Ashkenazi Jewish (ASJ)

AF:

0.0000612

AC:

AN:

16350

East Asian (EAS)

AF:

0.00

AC:

AN:

25844

South Asian (SAS)

AF:

0.000768

AC:

AN:

45562

European-Finnish (FIN)

AF:

0.00287

AC:

AN:

27854

Middle Eastern (MID)

AF:

0.000898

AC:

AN:

3340

European-Non Finnish (NFE)

AF:

0.00707

AC:

6945

AN:

983012

Other (OTH)

AF:

0.00467

AC:

223

AN:

47740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

421

842

1262

1683

2104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.00349

AC:

523

AN:

149920

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

245

AN XY:

73212

show subpopulations

African (AFR)

AF:

0.000971

AC:

AN:

41196

American (AMR)

AF:

0.00252

AC:

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

4960

South Asian (SAS)

AF:

0.000627

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00213

AC:

AN:

9840

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00612

AC:

412

AN:

67346

Other (OTH)

AF:

0.00384

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00346

Hom.:

Bravo

AF:

0.00340

ExAC

AF:

0.00177

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HCN1: PP3, BS2 -

May 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24747641) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Nov 16, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 19, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

Benign:1

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HCN1 NM_021072.3 exon 1 p.Gly47Val (c.140G>T):This variant has been reported in the literature in 1 individual with early infantile epileptic encephalopathy (Nava 2014 PMID:24747641). However this variant is present in 0.6% (412/67356) of European alleles including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-45695954-C-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign(Variation ID:193442). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Developmental and epileptic encephalopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HCN1-related disorder

Benign:1

Feb 23, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.0

N;.

PhyloP100

1.9

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.84

N;.

REVEL

Uncertain

0.38

Sift

Benign

0.20

T;.

Sift4G

Benign

0.27

T;T

Polyphen

0.36

B;.

Vest4

0.17

MVP

0.72

MPC

3.0

ClinPred

0.043

GERP RS

3.3

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.075

gMVP

0.31

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over