Genetic Variant HCN2:p.Pro36Leu (chr19-590052-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001194.4(HCN2):c.107C>T(p.Pro36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 20)

Exomes 𝑓: 0.017 ( 101 hom. )

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018992722).

BP6

Variant 19-590052-C-T is Benign according to our data. Variant chr19-590052-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2343084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0269 (3564/132590) while in subpopulation AMR AF = 0.0361 (502/13900). AF 95% confidence interval is 0.0335. There are 73 homozygotes in GnomAd4. There are 1743 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAd4 at 3564 AD gene.

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>T	p.Pro36Leu	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>T	p.Pro36Leu	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

3568

AN:

132614

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.0361

Gnomad AMR

AF:

0.0361

Gnomad ASJ

AF:

0.0552

Gnomad EAS

AF:

0.000469

Gnomad SAS

AF:

0.00939

Gnomad FIN

AF:

0.0237

Gnomad MID

AF:

0.0920

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0326

GnomAD4 exome

AF:

0.0166

AC:

8433

AN:

508956

Hom.:

101

Cov.:

AF XY:

0.0164

AC XY:

3909

AN XY:

238114

show subpopulations

African (AFR)

AF:

0.0212

AC:

208

AN:

9824

American (AMR)

AF:

0.0228

AC:

AN:

614

Ashkenazi Jewish (ASJ)

AF:

0.0448

AC:

139

AN:

3100

East Asian (EAS)

AF:

0.00

AC:

AN:

2204

South Asian (SAS)

AF:

0.00708

AC:

AN:

10314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

162

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

1000

European-Non Finnish (NFE)

AF:

0.0164

AC:

7631

AN:

465454

Other (OTH)

AF:

0.0205

AC:

334

AN:

16284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

302

604

905

1207

1509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<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

AF:

0.0269

AC:

3564

AN:

132590

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

1743

AN XY:

64438

show subpopulations

African (AFR)

AF:

0.0277

AC:

1024

AN:

36960

American (AMR)

AF:

0.0361

AC:

502

AN:

13900

Ashkenazi Jewish (ASJ)

AF:

0.0552

AC:

177

AN:

3206

East Asian (EAS)

AF:

0.000471

AC:

AN:

4242

South Asian (SAS)

AF:

0.00944

AC:

AN:

4238

European-Finnish (FIN)

AF:

0.0237

AC:

163

AN:

6872

Middle Eastern (MID)

AF:

0.0893

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.0257

AC:

1549

AN:

60356

Other (OTH)

AF:

0.0325

AC:

AN:

1844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

161

322

482

643

804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.00429

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

PhyloP100

0.27

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.066

gMVP

0.24

Mutation Taster

=87/13

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over