Variant 19-590052-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001194.4(HCN2):c.107C>T(p.Pro36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 20)

Exomes 𝑓: 0.017 ( 101 hom. )

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.272

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018992722).

BP6

Variant 19-590052-C-T is Benign according to our data. Variant chr19-590052-C-T is described in ClinVar as [Benign]. Clinvar id is 2343084.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0269 (3564/132590) while in subpopulation AMR AF= 0.0361 (502/13900). AF 95% confidence interval is 0.0335. There are 73 homozygotes in gnomad4. There are 1743 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3564 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4 linkuse as main transcript	c.107C>T	p.Pro36Leu	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 linkuse as main transcript	c.107C>T	p.Pro36Leu	missense_variant	1/8	1	NM_001194.4	ENSP00000251287.1		Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

3568

AN:

132614

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.0361

Gnomad AMR

AF:

0.0361

Gnomad ASJ

AF:

0.0552

Gnomad EAS

AF:

0.000469

Gnomad SAS

AF:

0.00939

Gnomad FIN

AF:

0.0237

Gnomad MID

AF:

0.0920

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0326

GnomAD4 exome

AF:

0.0166

AC:

8433

AN:

508956

Hom.:

101

Cov.:

AF XY:

0.0164

AC XY:

3909

AN XY:

238114

show subpopulations

Gnomad4 AFR exome

AF:

0.0212

Gnomad4 AMR exome

AF:

0.0228

Gnomad4 ASJ exome

AF:

0.0448

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00708

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0164

Gnomad4 OTH exome

AF:

0.0205

GnomAD4 genome

AF:

0.0269

AC:

3564

AN:

132590

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

1743

AN XY:

64438

show subpopulations

Gnomad4 AFR

AF:

0.0277

Gnomad4 AMR

AF:

0.0361

Gnomad4 ASJ

AF:

0.0552

Gnomad4 EAS

AF:

0.000471

Gnomad4 SAS

AF:

0.00944

Gnomad4 FIN

AF:

0.0237

Gnomad4 NFE

AF:

0.0257

Gnomad4 OTH

AF:

0.0325

Alfa

AF:

0.00429

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.079

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.39

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.87

Vest4

0.24

MutPred

0.31

Loss of glycosylation at P36 (P = 8e-04);

MVP

0.86

MPC

1.5

ClinPred

0.16

Varity_R

0.066

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

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