Genetic Variant HCN1:p.Pro43Arg (chr5-45695966-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021072.4(HCN1):c.128C>G(p.Pro43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000034 in 1,175,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P43S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HCN1
NM_021072.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.32

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20298222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.128C>G	p.Pro43Arg	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.128C>G	p.Pro43Arg	missense_variant	Exon 1 of 8	1	NM_021072.4	ENSP00000307342.4	O60741
HCN1	ENST00000673735.1 link	c.128C>G	p.Pro43Arg	missense_variant	Exon 1 of 9			ENSP00000501107.1	A0A669KB45
HCN1	ENST00000634658.1 link	c.128C>G	p.Pro43Arg	missense_variant	Exon 1 of 2	3		ENSP00000489134.1	A0A0U1RQR7
HCN1	ENST00000638054.1 link	n.-241C>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000340

AC:

AN:

1175170

Hom.:

Cov.:

AF XY:

0.00000523

AC XY:

AN XY:

573228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22862

American (AMR)

AF:

0.00

AC:

AN:

10174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16236

East Asian (EAS)

AF:

0.00

AC:

AN:

25306

South Asian (SAS)

AF:

0.00

AC:

AN:

44706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3272

European-Non Finnish (NFE)

AF:

0.00000409

AC:

AN:

977996

Other (OTH)

AF:

0.00

AC:

AN:

47228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.52

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.0

N;.

PhyloP100

2.3

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.3

N;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.018

D;.

Sift4G

Uncertain

0.0070

D;T

Polyphen

0.0

B;.

Vest4

0.092

MutPred

0.22

Gain of methylation at P43 (P = 0.01);Gain of methylation at P43 (P = 0.01);

MVP

0.51

MPC

2.6

ClinPred

0.47

GERP RS

3.0

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.13

gMVP

0.18

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over