Genetic Variant HCN2:p.Leu413Leu (chr19-607984-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001194.4(HCN2):c.1239G>C(p.Leu413Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,612,052 control chromosomes in the GnomAD database, including 6,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L413L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.12 ( 1367 hom., cov: 33)

Exomes 𝑓: 0.074 ( 4913 hom. )

Consequence

HCN2
NM_001194.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.76

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 19-607984-G-C is Benign according to our data. Variant chr19-607984-G-C is described in ClinVar as [Benign]. Clinvar id is 1226607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.76 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN2	NM_001194.4 link	c.1239G>C	p.Leu413Leu	synonymous_variant	Exon 4 of 8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3 link	c.1239G>C	p.Leu413Leu	synonymous_variant	Exon 4 of 8	1	NM_001194.4	ENSP00000251287.1		Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17669

AN:

152150

Hom.:

1364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.0878

Gnomad EAS

AF:

0.132

Gnomad SAS

AF:

0.0900

Gnomad FIN

AF:

0.0671

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0643

Gnomad OTH

AF:

0.103

GnomAD3 exomes

AF:

0.0932

AC:

23170

AN:

248694

Hom.:

1369

AF XY:

0.0893

AC XY:

12057

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.215

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.0866

Gnomad EAS exome

AF:

0.129

Gnomad SAS exome

AF:

0.0961

Gnomad FIN exome

AF:

0.0637

Gnomad NFE exome

AF:

0.0649

Gnomad OTH exome

AF:

0.0903

GnomAD4 exome

AF:

0.0743

AC:

108479

AN:

1459784

Hom.:

4913

Cov.:

AF XY:

0.0743

AC XY:

53961

AN XY:

726250

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.126

Gnomad4 ASJ exome

AF:

0.0839

Gnomad4 EAS exome

AF:

0.134

Gnomad4 SAS exome

AF:

0.0920

Gnomad4 FIN exome

AF:

0.0635

Gnomad4 NFE exome

AF:

0.0641

Gnomad4 OTH exome

AF:

0.0836

GnomAD4 genome

AF:

0.116

AC:

17709

AN:

152268

Hom.:

1367

Cov.:

AF XY:

0.118

AC XY:

8759

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.210

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.0878

Gnomad4 EAS

AF:

0.132

Gnomad4 SAS

AF:

0.0903

Gnomad4 FIN

AF:

0.0671

Gnomad4 NFE

AF:

0.0643

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0453

Hom.:

Bravo

AF:

0.124

EpiCase

AF:

0.0717

EpiControl

AF:

0.0695

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.22

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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