Genetic Variant HCN2:p.Pro27_Pro28dup (chr19-590007-G-GGCCGCC) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4BS1BS2

The NM_001194.4(HCN2):c.78_83dupGCCGCC(p.Pro27_Pro28dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0000039 ( 0 hom. )

Consequence

HCN2
NM_001194.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -6 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001194.4.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000063 (8/127068) while in subpopulation NFE AF = 0.000137 (8/58270). AF 95% confidence interval is 0.0000678. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 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.78_83dupGCCGCC	p.Pro27_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.78_83dupGCCGCC	p.Pro27_Pro28dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.0000630

AC:

AN:

127068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000137

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000389

AC:

AN:

513632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

240408

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

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:

0.00

AC:

AN:

10234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

974

European-Non Finnish (NFE)

AF:

0.00000426

AC:

AN:

469898

Other (OTH)

AF:

0.00

AC:

AN:

16618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

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:

0.0000630

AC:

AN:

127068

Hom.:

Cov.:

AF XY:

0.0000487

AC XY:

AN XY:

61640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35426

American (AMR)

AF:

0.00

AC:

AN:

13496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3146

East Asian (EAS)

AF:

0.00

AC:

AN:

3798

South Asian (SAS)

AF:

0.00

AC:

AN:

3850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.000137

AC:

AN:

58270

Other (OTH)

AF:

0.00

AC:

AN:

1748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000542

Hom.:

ClinVar

Not reported in ClinVar

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-GGCCGCCGCCGCCGCCGCCGCC

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