19-590072-C-T

Variant names:

• chr19-590072-C-T
• rs1313194590
• NM_001194.4:c.127C>T

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.127C>T​(p.Pro43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 580,922 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P43A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.937
• 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=0.20801559).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000223 (3/134468) while in subpopulation NFE AF = 0.0000491 (3/61122). AF 95% confidence interval is 0.000013. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 21. 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 38 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.127C>T	p.Pro43Ser	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.127C>T	p.Pro43Ser	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes AF: 0.0000223 AC: 3 AN: 134468 Hom.: 0 Cov.: 21

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: 0.0000491

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000851 AC: 38 AN: 446454 Hom.: 0 Cov.: 5 AF XY: 0.0000621 AC XY: 13 AN XY: 209416

African (AFR) AF: 0.00 AC: 0 AN: 8630

American (AMR) AF: 0.00 AC: 0 AN: 548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2770

East Asian (EAS) AF: 0.00 AC: 0 AN: 1962

South Asian (SAS) AF: 0.00 AC: 0 AN: 9336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 852

European-Non Finnish (NFE) AF: 0.0000858 AC: 35 AN: 407942

Other (OTH) AF: 0.000210 AC: 3 AN: 14278

GnomAD4 genome AF: 0.0000223 AC: 3 AN: 134468 Hom.: 0 Cov.: 21 AF XY: 0.0000153 AC XY: 1 AN XY: 65292

African (AFR) AF: 0.00 AC: 0 AN: 37430

American (AMR) AF: 0.00 AC: 0 AN: 13958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3236

East Asian (EAS) AF: 0.00 AC: 0 AN: 4398

South Asian (SAS) AF: 0.00 AC: 0 AN: 4362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000491 AC: 3 AN: 61122

Other (OTH) AF: 0.00 AC: 0 AN: 1832

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	0.092
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.94
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.12	N
REVEL	Uncertain	0.30
Sift	Benign	0.52	T
Sift4G	Uncertain	0.013	D
Polyphen		0.0	B
Vest4		0.23
MutPred		0.44		Gain of phosphorylation at P43 (P = 3e-04)
MVP		0.67
MPC		1.5
ClinPred		0.056	T
GERP RS		0.65
PromoterAI		-0.026	Neutral
Varity_R		0.034
gMVP		0.37
Mutation Taster		=94/6	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: rs1313194590; hg19: chr19-590072;