chr19-607984-G-C

Position:

• chr19-607984-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000251287.3(HCN2):​c.1239G>C​(p.Leu413=) 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 ENST00000251287.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.76

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]

ACMG classification

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/exons	MANE	Protein	UniProt
HCN2	NM_001194.4	c.1239G>C	p.Leu413=	synonymous_variant	4/8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3	c.1239G>C	p.Leu413=	synonymous_variant	4/8	1	NM_001194.4	ENSP00000251287	P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17669 AN: 152150 Hom.: 1364 Cov.: 33

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

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.: 32 AF XY: 0.0743 AC XY: 53961 AN XY: 726250

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.: 33 AF XY: 0.118 AC XY: 8759 AN XY: 74436

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.: 49

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2019	- -

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

Other links and lift over

dbSNP: rs3752158; hg19: chr19-607984; COSMIC: COSV52114904;