Genetic Variant HCN1:p.Ser9Pro (chr5-45696069-A-G) – ACMG Classification: Likely_benign (-1 pts)

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.25T>C	p.Ser9Pro	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.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 link	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000634658.1 link	c.25T>C	p.Ser9Pro	missense_variant	Exon 1 of 2	3		ENSP00000489134.1	A0A0U1RQR7

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 v4.3

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

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.90

L;.

PhyloP100

1.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.42

N;.

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

0.15

T;T

Polyphen

0.84

P;.

Vest4

0.13

MutPred

0.13

Loss of phosphorylation at S9 (P = 0.0054);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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over