21-34449472-C-G
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000219.6(KCNE1):c.163G>C(p.Gly55Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic 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. G55V) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 16)
Exomes 𝑓: 9.1e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNE1
NM_000219.6 missense
NM_000219.6 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 3.10
Publications
11 publications found
Genes affected
KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]
KCNE1 Gene-Disease associations (from GenCC):
- long QT syndrome 5Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- Jervell and Lange-Nielsen syndrome 2Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
- Jervell and Lange-Nielsen syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 104 uncertain in NM_000219.6
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
16
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251428 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
251428
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.10e-7 AC: 1AN: 1099244Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 557996 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1099244
Hom.:
Cov.:
21
AF XY:
AC XY:
0
AN XY:
557996
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
25198
American (AMR)
AF:
AC:
0
AN:
41434
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23262
East Asian (EAS)
AF:
AC:
0
AN:
36134
South Asian (SAS)
AF:
AC:
0
AN:
76408
European-Finnish (FIN)
AF:
AC:
0
AN:
51034
Middle Eastern (MID)
AF:
AC:
0
AN:
5142
European-Non Finnish (NFE)
AF:
AC:
1
AN:
792488
Other (OTH)
AF:
AC:
0
AN:
48144
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
16
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Apr 16, 2019
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Has not been previously published in association with arrhythmia to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17545244) -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D;D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;.;.;.;.;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);
MVP
MPC
0.47
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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