Genetic Variant HCN2:p.Ala16Thr (chr19-589991-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001194.4(HCN2):c.46G>A(p.Ala16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000024 ( 0 hom., cov: 19)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.171

Variant links:

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]

HCN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07225895).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000243 (3/123512) while in subpopulation AFR AF= 0.0000871 (3/34448). AF 95% confidence interval is 0.0000231. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 19. 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 rank	MANE	Protein	UniProt
HCN2	NM_001194.4 link	c.46G>A	p.Ala16Thr	missense_variant	Exon 1 of 8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3 link	c.46G>A	p.Ala16Thr	missense_variant	Exon 1 of 8	1	NM_001194.4	ENSP00000251287.1		Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.0000243

AC:

AN:

123512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000871

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000330

AC:

AN:

606430

Hom.:

Cov.:

AF XY:

0.00000353

AC XY:

AN XY:

283192

show subpopulations

Gnomad4 AFR exome

AF:

0.000175

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000243

AC:

AN:

123512

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

59816

show subpopulations

Gnomad4 AFR

AF:

0.0000871

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>A (p.A16T) alteration is located in exon 1 (coding exon 1) of the HCN2 gene. This alteration results from a G to A substitution at nucleotide position 46, causing the alanine (A) at amino acid position 16 to be replaced by a threonine (T). 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

0.097

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.22

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.32

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.072

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.080

REVEL

Benign

0.21

Sift

Benign

0.69

Sift4G

Benign

0.33

Polyphen

0.0010

Vest4

0.043

MutPred

0.22

Gain of phosphorylation at A16 (P = 0.0053);

MVP

0.44

MPC

1.5

ClinPred

0.045

GERP RS

0.17

Varity_R

0.033

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over