dbSNP rs868045953: HCN4:p.Ala23Ser (chr15-73368204-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000261917.4(HCN4):c.67G>T(p.Ala23Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A23T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HCN4
ENST00000261917.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.14

Publications

0 publications found

Variant links:

Genes affected

HCN4 (HGNC:16882): (hyperpolarization activated cyclic nucleotide gated potassium channel 4) This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]

HCN4 Gene-Disease associations (from GenCC):

sick sinus syndrome 2, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Brugada syndrome 8
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial sick sinus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

HCN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3849487).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261917.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	NM_005477.3	MANE Select	c.67G>T	p.Ala23Ser	missense	Exon 1 of 8	NP_005468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN4	ENST00000261917.4	TSL:1 MANE Select	c.67G>T	p.Ala23Ser	missense	Exon 1 of 8	ENSP00000261917.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1380736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682460

African (AFR)

AF:

0.00

AC:

AN:

28698

American (AMR)

AF:

0.00

AC:

AN:

35772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24388

East Asian (EAS)

AF:

0.00

AC:

AN:

33452

South Asian (SAS)

AF:

0.00

AC:

AN:

77690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073578

Other (OTH)

AF:

0.00

AC:

AN:

57230

GnomAD4 genome

Cov.:

Alfa

AF:

0.00189

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.38

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

1.7

PhyloP100

4.1

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.27

REVEL

Uncertain

0.42

Sift

Uncertain

0.011

Sift4G

Uncertain

0.041

Polyphen

0.90

Vest4

0.13

MutPred

0.18

Loss of sheet (P = 0.0126)

MVP

0.96

MPC

1.0

ClinPred

0.80

GERP RS

3.2

Varity_R

0.22

gMVP

0.45

Mutation Taster

=86/14

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