19-590082-G-C

Position:

• chr19-590082-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001194.4(HCN2):​c.137G>C​(p.Gly46Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12812656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4	c.137G>C	p.Gly46Ala	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.137G>C	p.Gly46Ala	missense_variant	1/8	1	NM_001194.4	ENSP00000251287.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.8
DANN	Benign	0.91
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.21		Loss of catalytic residue at G46 (P = 0.1126);
MVP		0.74
MPC		1.6
ClinPred		0.036	T
GERP RS		-0.63
Varity_R		0.028
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-590082;