dbSNP rs1060499864: HCN2:p.Ala778Thr (chr19-616136-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_001194.4(HCN2):c.2332G>A(p.Ala778Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000063 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HCN2
NM_001194.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.06

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=0.24323338).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000631 (15/237876) while in subpopulation AMR AF= 0.00309 (1/324). AF 95% confidence interval is 0.0000353. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 5. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN2	NM_001194.4 link	c.2332G>A	p.Ala778Thr	missense_variant	Exon 8 of 8	ENST00000251287.3	NP_001185.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN2	ENST00000251287.3 link	c.2332G>A	p.Ala778Thr	missense_variant	Exon 8 of 8	1	NM_001194.4	ENSP00000251287.1		Q9UL51

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

17452

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000631

AC:

AN:

237876

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

110346

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000598

Gnomad4 OTH exome

AF:

0.000127

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000115

AC:

AN:

17452

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

8406

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.23

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.24

REVEL

Benign

0.060

Sift

Benign

0.33

Sift4G

Benign

0.25

Polyphen

0.029

Vest4

0.085

MutPred

0.34

Gain of glycosylation at A778 (P = 4e-04);

MVP

0.54

MPC

1.1

ClinPred

0.095

GERP RS

1.0

Varity_R

0.029

gMVP

0.52

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over