Variant 1-155284728-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020897.3(HCN3):c.1060G>C(p.Asp354His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HCN3
NM_020897.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

HCN3 (HGNC:19183): (hyperpolarization activated cyclic nucleotide gated potassium channel 3) This gene encodes a multi-pass membrane protein that functions as a voltage gated cation channel. The encoded protein is a member of a family of closely related cyclic adenosine monophosphate-binding channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HCN3 links:

HCN3 (HGNC:):

HCN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCN3	NM_020897.3 linkuse as main transcript	c.1060G>C	p.Asp354His	missense_variant	4/8	ENST00000368358.4	NP_065948.1	Q9P1Z3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HCN3	ENST00000368358.4 linkuse as main transcript	c.1060G>C	p.Asp354His	missense_variant	4/8	1	NM_020897.3	ENSP00000357342.3	Q9P1Z3
HCN3	ENST00000467204.1 linkuse as main transcript	n.493G>C		non_coding_transcript_exon_variant	2/5	5
HCN3	ENST00000496230.5 linkuse as main transcript	n.1355G>C		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250788

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2024

The c.1060G>C (p.D354H) alteration is located in exon 4 (coding exon 4) of the HCN3 gene. This alteration results from a G to C substitution at nucleotide position 1060, causing the aspartic acid (D) at amino acid position 354 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.93

Vest4

0.97

MVP

0.99

MPC

0.73

ClinPred

0.98

GERP RS

5.3

Varity_R

0.85

gMVP

0.86

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