19-590052-C-G

Variant names:

• chr19-590052-C-G
• rs866177625
• NM_001194.4:c.107C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001194.4(HCN2):​c.107C>G​(p.Pro36Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P36L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31155598).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	NM_001194.4	MANE Select	c.107C>G	p.Pro36Arg	missense	Exon 1 of 8	NP_001185.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.107C>G	p.Pro36Arg	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes AF: 0.00000754 AC: 1 AN: 132640 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000720

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 509392 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 238296

African (AFR) AF: 0.00 AC: 0 AN: 9838

American (AMR) AF: 0.00 AC: 0 AN: 614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3104

East Asian (EAS) AF: 0.00 AC: 0 AN: 2204

South Asian (SAS) AF: 0.00 AC: 0 AN: 10314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1002

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 465856

Other (OTH) AF: 0.00 AC: 0 AN: 16298

GnomAD4 genome AF: 0.00000754 AC: 1 AN: 132616 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 64448

African (AFR) AF: 0.00 AC: 0 AN: 36962

American (AMR) AF: 0.0000719 AC: 1 AN: 13902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3208

East Asian (EAS) AF: 0.00 AC: 0 AN: 4242

South Asian (SAS) AF: 0.00 AC: 0 AN: 4238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60374

Other (OTH) AF: 0.00 AC: 0 AN: 1844

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Benign	0.68
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.24	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.20	N
PhyloP100		0.27
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.030	N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.18
MutPred		0.29		Loss of glycosylation at P36 (P = 8e-04)
MVP		0.78
MPC		1.6
ClinPred		0.14	T
PromoterAI		0.044	Neutral
Varity_R		0.087
gMVP		0.27
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs866177625; hg19: chr19-590052;