Variant 19-590366-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001194.4(HCN2):c.421G>T(p.Ala141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,153,368 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A141V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0055 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 43 hom. )

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.42

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013861954).

BP6

Variant 19-590366-G-T is Benign according to our data. Variant chr19-590366-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2343234.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 818 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN2	NM_001194.4 linkuse as main transcript	c.421G>T	p.Ala141Ser	missense_variant	1/8	ENST00000251287.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN2	ENST00000251287.3 linkuse as main transcript	c.421G>T	p.Ala141Ser	missense_variant	1/8	1	NM_001194.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00554

AC:

818

AN:

147642

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00610

Gnomad ASJ

AF:

0.00205

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00288

Gnomad MID

AF:

0.00654

Gnomad NFE

AF:

0.00942

Gnomad OTH

AF:

0.00442

GnomAD3 exomes

AF:

0.00743

AC:

AN:

2018

Hom.:

AF XY:

0.00611

AC XY:

AN XY:

1146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0577

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00617

Gnomad NFE exome

AF:

0.00822

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00774

AC:

7785

AN:

1005616

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

3735

AN XY:

474724

show subpopulations

Gnomad4 AFR exome

AF:

0.000945

Gnomad4 AMR exome

AF:

0.00557

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000259

Gnomad4 FIN exome

AF:

0.00318

Gnomad4 NFE exome

AF:

0.00849

Gnomad4 OTH exome

AF:

0.00614

GnomAD4 genome

AF:

0.00554

AC:

818

AN:

147752

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

368

AN XY:

72056

show subpopulations

Gnomad4 AFR

AF:

0.00139

Gnomad4 AMR

AF:

0.00609

Gnomad4 ASJ

AF:

0.00205

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00288

Gnomad4 NFE

AF:

0.00943

Gnomad4 OTH

AF:

0.00437

Alfa

AF:

0.00589

Hom.:

Bravo

AF:

0.00537

ExAC

AF:

0.00283

AC:

143

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2021

This alteration is classified as likely 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

0.084

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.18

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0014

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.89

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.090

REVEL

Uncertain

0.33

Sift

Benign

0.43

Sift4G

Benign

0.86

Polyphen

0.043

Vest4

0.061

MVP

0.72

MPC

1.4

ClinPred

0.020

GERP RS

0.99

Varity_R

0.073

gMVP

0.20

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