dbSNP rs12374423: HCN1:c.850-68513G>T (chr5-45530520-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_021072.4(HCN1):c.850-68513G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 151,166 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 67 hom., cov: 31)

Consequence

HCN1
NM_021072.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.730

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: 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0217 (3287/151166) while in subpopulation NFE AF = 0.0306 (2075/67802). AF 95% confidence interval is 0.0295. There are 67 homozygotes in GnomAd4. There are 1644 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 3287 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN1	NM_021072.4 link	c.850-68513G>T		intron_variant	Intron 2 of 7	ENST00000303230.6	NP_066550.2	O60741Q86WJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN1	ENST00000303230.6 link	c.850-68513G>T		intron_variant	Intron 2 of 7	1	NM_021072.4	ENSP00000307342.4		O60741
HCN1	ENST00000673735.1 link	c.850-68513G>T		intron_variant	Intron 2 of 8			ENSP00000501107.1		A0A669KB45

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3287

AN:

151064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00445

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.0670

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.0306

Gnomad OTH

AF:

0.0207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0217

AC:

3287

AN:

151166

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1644

AN XY:

73800

show subpopulations

African (AFR)

AF:

0.00441

AC:

182

AN:

41252

American (AMR)

AF:

0.0120

AC:

182

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00167

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.0670

AC:

686

AN:

10240

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0306

AC:

2075

AN:

67802

Other (OTH)

AF:

0.0205

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

157

314

471

628

785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0290

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.00203

AC:

AN:

3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.99

(source)

DANN

Benign

0.44

PhyloP100

-0.73

Mutation Taster

=100/0

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