Genetic Variant NM_001194.4:c.107C>G (chr19-590052-C-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001194.4(HCN2):c.107C>G(p.Pro36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P36L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000075 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.272

Publications

1 publications found

Variant links:

Genes affected

HCN2 (HGNC:4846): (hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2) The protein encoded by this gene is a hyperpolarization-activated cation channel involved in the generation of native pacemaker activity in the heart and in the brain. The encoded protein is activated by cAMP and can produce a fast, large current. Defects in this gene were noted as a possible cause of some forms of epilepsy. [provided by RefSeq, Jan 2017]

HCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31155598).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	NM_001194.4	MANE Select	c.107C>G	p.Pro36Arg	missense	Exon 1 of 8	NP_001185.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.107C>G	p.Pro36Arg	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.00000754

AC:

AN:

132640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

509392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

238296

African (AFR)

AF:

0.00

AC:

AN:

9838

American (AMR)

AF:

0.00

AC:

AN:

614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3104

East Asian (EAS)

AF:

0.00

AC:

AN:

2204

South Asian (SAS)

AF:

0.00

AC:

AN:

10314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1002

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

465856

Other (OTH)

AF:

0.00

AC:

AN:

16298

GnomAD4 genome

AF:

0.00000754

AC:

AN:

132616

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36962

American (AMR)

AF:

0.0000719

AC:

AN:

13902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3208

East Asian (EAS)

AF:

0.00

AC:

AN:

4242

South Asian (SAS)

AF:

0.00

AC:

AN:

4238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60374

Other (OTH)

AF:

0.00

AC:

AN:

1844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.21

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.24

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

0.20

PhyloP100

0.27

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.030

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.99

Vest4

0.18

MutPred

0.29

Loss of glycosylation at P36 (P = 8e-04)

MVP

0.78

MPC

1.6

ClinPred

0.14

PromoterAI

0.044

Neutral

(source)

Varity_R

0.087

gMVP

0.27

Mutation Taster

=84/16

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over