19-590159-C-T

Variant names:

• chr19-590159-C-T
• rs1380703459
• NM_001194.4:c.214C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001194.4(HCN2):​c.214C>T​(p.Arg72Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 974,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.102
• Publications: 0 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17728642).
• BS2: High AC in GnomAd4 at 9 AD gene.

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.214C>T	p.Arg72Trp	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.214C>T	p.Arg72Trp	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes AF: 0.0000631 AC: 9 AN: 142652 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00268

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 10 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 12 AN: 832256 Hom.: 0 Cov.: 21 AF XY: 0.0000104 AC XY: 4 AN XY: 385038

African (AFR) AF: 0.00 AC: 0 AN: 15744

American (AMR) AF: 0.00 AC: 0 AN: 1024

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 9 AN: 5166

East Asian (EAS) AF: 0.00 AC: 0 AN: 3662

South Asian (SAS) AF: 0.00 AC: 0 AN: 17264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1632

European-Non Finnish (NFE) AF: 0.00000263 AC: 2 AN: 760130

Other (OTH) AF: 0.0000366 AC: 1 AN: 27298

GnomAD4 genome AF: 0.0000631 AC: 9 AN: 142652 Hom.: 0 Cov.: 23 AF XY: 0.000101 AC XY: 7 AN XY: 69336

African (AFR) AF: 0.00 AC: 0 AN: 39876

American (AMR) AF: 0.00 AC: 0 AN: 14574

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 9 AN: 3362

East Asian (EAS) AF: 0.00 AC: 0 AN: 4814

South Asian (SAS) AF: 0.00 AC: 0 AN: 4710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64248

Other (OTH) AF: 0.00 AC: 0 AN: 1974

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.69	N
PhyloP100		0.10
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.028	D
Polyphen		0.98	D
Vest4		0.059
MutPred		0.30		Loss of methylation at R72 (P = 0.0122)
MVP		0.51
MPC		1.6
ClinPred		0.58	D
GERP RS		0.65
PromoterAI		-0.018	Neutral
Varity_R		0.12
gMVP		0.32
Mutation Taster		=87/13	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: rs1380703459; hg19: chr19-590159;