19-590198-C-T

Position:

• chr19-590198-C-T

Variant summary

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

The NM_001194.4(HCN2):​c.253C>T​(p.Pro85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 838,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0250

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=0.151173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4	c.253C>T	p.Pro85Ser	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.253C>T	p.Pro85Ser	missense_variant	1/8	1	NM_001194.4	ENSP00000251287.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000358 AC: 3 AN: 838622 Hom.: 0 Cov.: 29 AF XY: 0.00000515 AC XY: 2 AN XY: 388432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000392

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2024

The c.253C>T (p.P85S) alteration is located in exon 1 (coding exon 1) of the HCN2 gene. This alteration results from a C to T substitution at nucleotide position 253, causing the proline (P) at amino acid position 85 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.0057	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.14	T
Polyphen		0.049	B
Vest4		0.030
MutPred		0.17		Gain of phosphorylation at P85 (P = 0.0069);
MVP		0.76
MPC		1.5
ClinPred		0.053	T
Varity_R		0.052
gMVP		0.23

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: chr19-590198;