Genetic Variant HCN2:p.Pro28dup (chr19-590007-G-GGCC) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PM4_SupportingBP6_ModerateBS1BS2

The NM_001194.4(HCN2):c.81_83dupGCC(p.Pro28dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 20)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

HCN2
NM_001194.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.460

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001194.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 19-590007-G-GGCC is Benign according to our data. Variant chr19-590007-G-GGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 2357092.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000882 (112/127052) while in subpopulation AFR AF = 0.00282 (100/35458). AF 95% confidence interval is 0.00237. There are 1 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAd4 at 112 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.81_83dupGCC	p.Pro28dup	disruptive_inframe_insertion	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.81_83dupGCC	p.Pro28dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.000866

AC:

110

AN:

127064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000370

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000527

Gnomad SAS

AF:

0.000779

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000343

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

513590

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

240392

show subpopulations

African (AFR)

AF:

0.00175

AC:

AN:

9704

American (AMR)

AF:

0.00

AC:

AN:

642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3182

East Asian (EAS)

AF:

0.00

AC:

AN:

2216

South Asian (SAS)

AF:

0.0000977

AC:

AN:

10232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

974

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

469858

Other (OTH)

AF:

0.000241

AC:

AN:

16618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.402

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

AF:

0.000882

AC:

112

AN:

127052

Hom.:

Cov.:

AF XY:

0.000973

AC XY:

AN XY:

61642

show subpopulations

African (AFR)

AF:

0.00282

AC:

100

AN:

35458

American (AMR)

AF:

0.000370

AC:

AN:

13510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3146

East Asian (EAS)

AF:

0.000529

AC:

AN:

3782

South Asian (SAS)

AF:

0.000782

AC:

AN:

3834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000343

AC:

AN:

58262

Other (OTH)

AF:

0.00

AC:

AN:

1752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000542

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.46

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-590007-GGCCGCCGCCGCCGCC-GGCCGCCGCCGCCGCCGCC

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