19-590323-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001194.4(HCN2):c.378G>T(p.Ser126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,022,050 control chromosomes in the GnomAD database, including 3,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.095 (976 hom., cov: 30)
  • Exomes 𝑓: 0.069 (2374 hom.)
• Consequence: HCN2 NM_001194.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-590323-G-T is Benign according to our data. Variant chr19-590323-G-T is described in ClinVar as [Benign]. Clinvar id is 1226483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN2	NM_001194.4	c.378G>T	p.Ser126=	synonymous_variant	1/8	ENST00000251287.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN2	ENST00000251287.3	c.378G>T	p.Ser126=	synonymous_variant	1/8	1	NM_001194.4	P1

Frequencies

GnomAD3 genomes AF: 0.0945 AC: 13726 AN: 145252 Hom.: 971 Cov.: 30

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00447

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0344

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0357

Gnomad NFE AF: 0.0579

Gnomad OTH AF: 0.0762

GnomAD3 exomes AF: 0.0375 AC: 6 AN: 160 Hom.: 0 AF XY: 0.0476 AC XY: 4 AN XY: 84

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0612

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0688 AC: 60289 AN: 876694 Hom.: 2374 Cov.: 28 AF XY: 0.0689 AC XY: 28170 AN XY: 409068

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0519

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.0431

Gnomad4 SAS exome AF: 0.0921

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.0660

Gnomad4 OTH exome AF: 0.0715

GnomAD4 genome AF: 0.0946 AC: 13752 AN: 145356 Hom.: 976 Cov.: 30 AF XY: 0.0916 AC XY: 6479 AN XY: 70732

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0575

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.0345

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0579

Gnomad4 OTH AF: 0.0779

Alfa AF: 0.0769 Hom.: 66

Bravo AF: 0.0986

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

GeneDx

Feb 04, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	9.2
Dann	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs186019555; hg19: chr19-590323; COSMIC: COSV105862803; COSMIC: COSV105862803;