15-73322684-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000261917.4(HCN4):​c.3409C>A​(p.Pro1137Thr) 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. 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. P1137S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HCN4
ENST00000261917.4 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.91
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20260388).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HCN4NM_005477.3 linkuse as main transcriptc.3409C>A p.Pro1137Thr missense_variant 8/8 ENST00000261917.4 NP_005468.1
HCN4XM_011521148.3 linkuse as main transcriptc.2191C>A p.Pro731Thr missense_variant 7/7 XP_011519450.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HCN4ENST00000261917.4 linkuse as main transcriptc.3409C>A p.Pro1137Thr missense_variant 8/81 NM_005477.3 ENSP00000261917 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1439942
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
714118
Gnomad4 AFR exome
AF:
0.00
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
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
11
DANN
Benign
0.96
DEOGEN2
Benign
0.23
T
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.52
T
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.20
T
MetaSVM
Uncertain
0.11
D
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.46
N
REVEL
Benign
0.26
Sift
Benign
0.28
T
Sift4G
Benign
0.39
T
Polyphen
0.072
B
Vest4
0.18
MutPred
0.25
Gain of phosphorylation at P1137 (P = 0.0047);
MVP
0.79
MPC
0.70
ClinPred
0.24
T
GERP RS
3.0
Varity_R
0.048
gMVP
0.26

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.

Other links and lift over

dbSNP: rs773914774; hg19: chr15-73615025; API