Genetic Variant NM_001194.4:c.81_83delGCC (chr19-590007-GGCC-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PM4_SupportingBP6_Moderate

The NM_001194.4(HCN2):c.81_83delGCC(p.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 0.00189 in 637,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0024 ( 0 hom. )

Consequence

HCN2
NM_001194.4 disruptive_inframe_deletion

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: Likely_benign. The variant received -1 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-GGCC-G is Benign according to our data. Variant chr19-590007-GGCC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3283623.Status of the report is criteria_provided_single_submitter, 1 stars.

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_83delGCC	p.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.81_83delGCC	p.Pro28del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.0000157

AC:

AN:

127068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000282

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:

0.0000172

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00236

AC:

1202

AN:

510382

Hom.:

AF XY:

0.00242

AC XY:

577

AN XY:

238880

show subpopulations

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

African (AFR)

AF:

0.00207

AC:

AN:

9666

American (AMR)

AF:

0.00469

AC:

AN:

640

Ashkenazi Jewish (ASJ)

AF:

0.00190

AC:

AN:

3158

East Asian (EAS)

AF:

0.00182

AC:

AN:

2202

South Asian (SAS)

AF:

0.00275

AC:

AN:

10168

European-Finnish (FIN)

AF:

0.00610

AC:

AN:

164

Middle Eastern (MID)

AF:

0.00412

AC:

AN:

970

European-Non Finnish (NFE)

AF:

0.00235

AC:

1097

AN:

466900

Other (OTH)

AF:

0.00236

AC:

AN:

16514

⚠️ 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: 0.255

Heterozygous variant carriers

162

324

485

647

809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

180

240

300

<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:

0.0000157

AC:

AN:

127068

Hom.:

Cov.:

AF XY:

0.0000162

AC XY:

AN XY:

61640

show subpopulations

African (AFR)

AF:

0.0000282

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:

0.0000172

AC:

AN:

58270

Other (OTH)

AF:

0.00

AC:

AN:

1748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

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

=82/18

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

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

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