19-589962-G-T

Position:

• chr19-589962-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001194.4(HCN2):​c.17G>T​(p.Gly6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.299

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32616913).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4	c.17G>T	p.Gly6Val	missense_variant	1/8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3	c.17G>T	p.Gly6Val	missense_variant	1/8	1	NM_001194.4	ENSP00000251287.1

Frequencies

GnomAD3 genomes AF: 0.0000387 AC: 5 AN: 129100 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0000278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000292

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 14 AN: 788626 Hom.: 0 Cov.: 13 AF XY: 0.0000137 AC XY: 5 AN XY: 365218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000387 AC: 5 AN: 129100 Hom.: 0 Cov.: 19 AF XY: 0.0000320 AC XY: 2 AN XY: 62574

Gnomad4 AFR AF: 0.0000278

Gnomad4 AMR AF: 0.000292

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.064	T
Polyphen		0.95	P
Vest4		0.17
MutPred		0.24		Gain of MoRF binding (P = 0.052);
MVP		0.56
MPC		1.8
ClinPred		0.17	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.20

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: rs1199254032; hg19: chr19-589962;