NM_021072.4:c.25T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4BP6_Moderate

The NM_021072.4(HCN1):c.25T>C(p.Ser9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000832 in 1,202,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S9S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.51

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28020924).

BP6

Variant 5-45696069-A-G is Benign according to our data. Variant chr5-45696069-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 530572.Status of the report is criteria_provided_single_submitter, 1 stars.

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.25T>C	p.Ser9Pro	missense	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.25T>C	p.Ser9Pro	missense	Exon 1 of 8	ENSP00000307342.4
HCN1	ENST00000673735.1		c.25T>C	p.Ser9Pro	missense	Exon 1 of 9	ENSP00000501107.1
HCN1	ENST00000634658.1	TSL:3	c.25T>C	p.Ser9Pro	missense	Exon 1 of 2	ENSP00000489134.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.32e-7

AC:

AN:

1202204

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

592086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24022

American (AMR)

AF:

0.0000444

AC:

AN:

22512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18826

East Asian (EAS)

AF:

0.00

AC:

AN:

21030

South Asian (SAS)

AF:

0.00

AC:

AN:

63436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3610

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

974234

Other (OTH)

AF:

0.00

AC:

AN:

46464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.90

PhyloP100

1.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.42

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Benign

0.15

Polyphen

0.84

Vest4

0.13

MutPred

0.13

Loss of phosphorylation at S9 (P = 0.0054)

MVP

0.82

MPC

2.2

ClinPred

0.43

GERP RS

3.2

PromoterAI

0.051

Neutral

(source)

Varity_R

0.22

gMVP

0.49

Mutation Taster

=76/24

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over