Variant 19-590172-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001194.4(HCN2):c.227G>A(p.Arg76His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 976,302 control chromosomes in the GnomAD database, including 118,627 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 Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12023 hom., cov: 25)

Exomes 𝑓: 0.50 ( 106604 hom. )

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.378

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012045503).

BP6

Variant 19-590172-G-A is Benign according to our data. Variant chr19-590172-G-A is described in ClinVar as [Benign]. Clinvar id is 1291938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN2	NM_001194.4 linkuse as main transcript	c.227G>A	p.Arg76His	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.227G>A	p.Arg76His	missense_variant	1/8	1	NM_001194.4	ENSP00000251287.1		Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.388

AC:

54896

AN:

141624

Hom.:

12026

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.461

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.417

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.512

Gnomad MID

AF:

0.365

Gnomad NFE

AF:

0.513

Gnomad OTH

AF:

0.401

GnomAD3 exomes

AF:

0.438

AC:

AN:

Hom.:

AF XY:

0.333

AC XY:

AN XY:

show subpopulations

Gnomad AMR exome

AF:

0.500

Gnomad SAS exome

AF:

0.167

Gnomad NFE exome

AF:

0.625

GnomAD4 exome

AF:

0.501

AC:

418067

AN:

834610

Hom.:

106604

Cov.:

AF XY:

0.500

AC XY:

193093

AN XY:

386144

show subpopulations

Gnomad4 AFR exome

AF:

0.163

Gnomad4 AMR exome

AF:

0.383

Gnomad4 ASJ exome

AF:

0.418

Gnomad4 EAS exome

AF:

0.309

Gnomad4 SAS exome

AF:

0.274

Gnomad4 FIN exome

AF:

0.582

Gnomad4 NFE exome

AF:

0.516

Gnomad4 OTH exome

AF:

0.458

GnomAD4 genome

AF:

0.387

AC:

54891

AN:

141692

Hom.:

12023

Cov.:

AF XY:

0.382

AC XY:

26336

AN XY:

68882

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.370

Gnomad4 ASJ

AF:

0.417

Gnomad4 EAS

AF:

0.294

Gnomad4 SAS

AF:

0.270

Gnomad4 FIN

AF:

0.512

Gnomad4 NFE

AF:

0.513

Gnomad4 OTH

AF:

0.399

Alfa

AF:

0.445

Hom.:

2046

TwinsUK

AF:

0.536

AC:

1987

ALSPAC

AF:

0.539

AC:

2079

ExAC

AF:

0.170

AC:

237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0012

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.31

REVEL

Benign

0.26

Sift

Benign

0.26

Sift4G

Benign

0.28

Polyphen

0.20

Vest4

0.031

MPC

1.8

ClinPred

0.033

GERP RS

0.65

Varity_R

0.056

gMVP

0.26

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