rs3752158

Positions:

• chr19-607984-G-A
• chr19-607984-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001194.4(HCN2):​c.1239G>A​(p.Leu413=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,612,242 control chromosomes in the GnomAD database, including 20 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 0.00088 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (19 hom.)
• Consequence: HCN2 NM_001194.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-607984-G-A is Benign according to our data. Variant chr19-607984-G-A is described in ClinVar as [Benign]. Clinvar id is 769444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BS2: High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN2	NM_001194.4	c.1239G>A	p.Leu413=	synonymous_variant	4/8	ENST00000251287.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00150 AC: 373 AN: 248694 Hom.: 3 AF XY: 0.00196 AC XY: 264 AN XY: 135008

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00830

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000726

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.00118 AC: 1729 AN: 1459940 Hom.: 19 Cov.: 32 AF XY: 0.00141 AC XY: 1022 AN XY: 726298

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00902

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000716

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.000954 AC XY: 71 AN XY: 74460

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000469 Hom.: 49

EpiCase AF: 0.00104

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.26
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;