Genetic Variant HCN2:p.Pro31His (chr19-590037-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001194.4(HCN2):c.92C>A(p.Pro31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 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. P31R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.12

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20293239).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000823 (4/486268) while in subpopulation AFR AF = 0.000215 (2/9312). AF 95% confidence interval is 0.0000374. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 6. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.92C>A	p.Pro31His	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.92C>A	p.Pro31His	missense	Exon 1 of 8	ENSP00000251287.1	Q9UL51

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000823

AC:

AN:

486268

Hom.:

Cov.:

AF XY:

0.00000878

AC XY:

AN XY:

227700

show subpopulations

African (AFR)

AF:

0.000215

AC:

AN:

9312

American (AMR)

AF:

0.00

AC:

AN:

592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3052

East Asian (EAS)

AF:

0.00

AC:

AN:

2072

South Asian (SAS)

AF:

0.00

AC:

AN:

9694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

958

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

444734

Other (OTH)

AF:

0.00

AC:

AN:

15704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.23

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.20

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.051

MutationAssessor

Benign

0.55

PhyloP100

-1.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.13

REVEL

Benign

0.29

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

0.84

Vest4

0.14

MutPred

0.23

Loss of glycosylation at P31 (P = 0.0111)

MVP

0.49

MPC

1.7

ClinPred

0.15

GERP RS

1.1

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.15

gMVP

0.24

Mutation Taster

=89/11

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over