19-590000-G-A

Variant names:

• chr19-590000-G-A
• rs1322574294
• NM_001194.4:c.55G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001194.4(HCN2):​c.55G>A​(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000025 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0550
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14125055).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000246 (3/122014) while in subpopulation NFE AF = 0.0000528 (3/56784). AF 95% confidence interval is 0.000014. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 11 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.55G>A	p.Ala19Thr	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.55G>A	p.Ala19Thr	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes AF: 0.0000246 AC: 3 AN: 122014 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000528

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 11 AN: 574510 Hom.: 0 Cov.: 7 AF XY: 0.00000745 AC XY: 2 AN XY: 268476

African (AFR) AF: 0.00 AC: 0 AN: 10870

American (AMR) AF: 0.00 AC: 0 AN: 700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3548

East Asian (EAS) AF: 0.00 AC: 0 AN: 2438

South Asian (SAS) AF: 0.00 AC: 0 AN: 11480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1098

European-Non Finnish (NFE) AF: 0.0000209 AC: 11 AN: 525656

Other (OTH) AF: 0.00 AC: 0 AN: 18530

GnomAD4 genome AF: 0.0000246 AC: 3 AN: 122014 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 58952

African (AFR) AF: 0.00 AC: 0 AN: 34122

American (AMR) AF: 0.00 AC: 0 AN: 13036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3090

East Asian (EAS) AF: 0.00 AC: 0 AN: 3204

South Asian (SAS) AF: 0.00 AC: 0 AN: 3358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000528 AC: 3 AN: 56784

Other (OTH) AF: 0.00 AC: 0 AN: 1712

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	0.096
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.0071	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.055
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.20
Sift	Benign	0.33	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.058
MutPred		0.31		Gain of phosphorylation at A19 (P = 2e-04)
MVP		0.63
MPC		1.5
ClinPred		0.035	T
GERP RS		-4.0
PromoterAI		-0.013	Neutral
Varity_R		0.062
gMVP		0.20
Mutation Taster		=99/1	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: rs1322574294; hg19: chr19-590000;