19-590037-C-A

Position:

• chr19-590037-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001194.4(HCN2):​c.92C>A​(p.Pro31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: HCN2 NM_001194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.12

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20293239).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000823 (4/486268) while in subpopulation AFR AF= 0.000215 (2/9312). AF 95% confidence interval is 0.0000374. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 6. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4	c.92C>A	p.Pro31His	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.92C>A	p.Pro31His	missense_variant	1/8	1	NM_001194.4	ENSP00000251287.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000823 AC: 4 AN: 486268 Hom.: 0 Cov.: 6 AF XY: 0.00000878 AC XY: 2 AN XY: 227700

Gnomad4 AFR exome AF: 0.000215

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

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

May 02, 2024

The c.92C>A (p.P31H) alteration is located in exon 1 (coding exon 1) of the HCN2 gene. This alteration results from a C to A substitution at nucleotide position 92, causing the proline (P) at amino acid position 31 to be replaced by a histidine (H). 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	0.18
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.20	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.84	P
Vest4		0.14
MutPred		0.23		Loss of glycosylation at P31 (P = 0.0111);
MVP		0.49
MPC		1.7
ClinPred		0.15	T
GERP RS		1.1
Varity_R		0.15
gMVP		0.24

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: chr19-590037;