Variant 19-590007-G-GGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4 link	c.81_83dupGCC	p.Pro28dup	disruptive_inframe_insertion	1/8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3 link	c.81_83dupGCC	p.Pro28dup	disruptive_inframe_insertion	1/8	1	NM_001194.4	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

Gnomad4 AFR exome

AF:

0.00175

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000977

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000241

GnomAD4 genome

AF:

0.000882

AC:

112

AN:

127052

Hom.:

Cov.:

AF XY:

0.000973

AC XY:

AN XY:

61642

show subpopulations

Gnomad4 AFR

AF:

0.00282

Gnomad4 AMR

AF:

0.000370

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000529

Gnomad4 SAS

AF:

0.000782

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000343

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over