Genetic Variant HCN2:p.Pro27_Pro28del (chr19-590007-GGCCGCC-G) – 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_83delGCCGCC(p.Pro27_Pro28del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 640,344 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

HCN2
NM_001194.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

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:

Genome browser will be placed here

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 amr. GnomAd4 allele frequency = 0.0000394 (5/127056) while in subpopulation AMR AF = 0.000074 (1/13510). AF 95% confidence interval is 0.00000934. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAd4 at 5 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_83delGCCGCC	p.Pro27_Pro28del	disruptive_inframe_deletion	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_83delGCCGCC	p.Pro27_Pro28del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.0000393

AC:

AN:

127068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000565

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000741

Gnomad ASJ

AF:

0.000636

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

AF:

0.000134

AC:

AN:

513288

Hom.:

AF XY:

0.000154

AC XY:

AN XY:

240246

show subpopulations

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

African (AFR)

AF:

0.000206

AC:

AN:

9700

American (AMR)

AF:

0.00

AC:

AN:

642

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

3178

East Asian (EAS)

AF:

0.00

AC:

AN:

2214

South Asian (SAS)

AF:

0.000293

AC:

AN:

10226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

164

Middle Eastern (MID)

AF:

0.00103

AC:

AN:

974

European-Non Finnish (NFE)

AF:

0.000115

AC:

AN:

469580

Other (OTH)

AF:

0.000181

AC:

AN:

16610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.264

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:

0.0000394

AC:

AN:

127056

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

61646

show subpopulations

African (AFR)

AF:

0.0000564

AC:

AN:

35462

American (AMR)

AF:

0.0000740

AC:

AN:

13510

Ashkenazi Jewish (ASJ)

AF:

0.000636

AC:

AN:

3146

East Asian (EAS)

AF:

0.00

AC:

AN:

3782

South Asian (SAS)

AF:

0.00

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:

0.00

AC:

AN:

58262

Other (OTH)

AF:

0.00

AC:

AN:

1752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

PhyloP100

1.1

Mutation Taster

=163/37

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-590007-GGCCGCCGCCGCCGCC-GGCCGCCGCC

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