Genetic Variant NM_001194.4:c.250C>T (chr19-590195-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001194.4(HCN2):c.250C>T(p.Arg84Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.921

Publications

0 publications found

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:

ENSG00000267036 (HGNC:):

ENSG00000267036 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22244963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	NM_001194.4	MANE Select	c.250C>T	p.Arg84Cys	missense	Exon 1 of 8	NP_001185.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN2	ENST00000251287.3	TSL:1 MANE Select	c.250C>T	p.Arg84Cys	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51
	ENSG00000267036	ENST00000589661.2	TSL:6	n.*235G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

837826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

387932

African (AFR)

AF:

0.00

AC:

AN:

15832

American (AMR)

AF:

0.00

AC:

AN:

1076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5220

East Asian (EAS)

AF:

0.00

AC:

AN:

3724

South Asian (SAS)

AF:

0.00

AC:

AN:

17386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1644

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

764980

Other (OTH)

AF:

0.00

AC:

AN:

27496

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.0014

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.028

MutationAssessor

Benign

0.34

PhyloP100

0.92

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.62

REVEL

Benign

0.28

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.027

Polyphen

0.89

Vest4

0.11

MutPred

0.30

Loss of MoRF binding (P = 0.0031)

MVP

0.67

MPC

1.9

ClinPred

0.34

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.095

gMVP

0.28

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over