NM_172201.2:c.357C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_172201.2(KCNE2):​c.357C>A​(p.Phe119Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.431

Publications

0 publications found
Variant links:
Genes affected
KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]
KCNE2 Gene-Disease associations (from GenCC):
  • familial atrial fibrillation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • long QT syndrome 6
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
  • long QT syndrome
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.09317413).
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNE2NM_172201.2 linkc.357C>A p.Phe119Leu missense_variant Exon 2 of 2 ENST00000290310.4 NP_751951.1 Q9Y6J6
LOC105372791NR_188571.1 linkn.452G>T non_coding_transcript_exon_variant Exon 2 of 3
LOC105372791NR_188572.1 linkn.452G>T non_coding_transcript_exon_variant Exon 2 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNE2ENST00000290310.4 linkc.357C>A p.Phe119Leu missense_variant Exon 2 of 2 1 NM_172201.2 ENSP00000290310.2 Q9Y6J6

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251274
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461710
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727160
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5632
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1112012
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.461
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74344
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41434
American (AMR)
AF:
0.0000655
AC:
1
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Long QT syndrome 6 Uncertain:1
Mar 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 119 of the KCNE2 protein (p.Phe119Leu). This variant is present in population databases (rs139202426, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with KCNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 191467). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1
Feb 12, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.F119L variant (also known as c.357C>A), located in coding exon 1 of the KCNE2 gene, results from a C to A substitution at nucleotide position 357. The phenylalanine at codon 119 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). Additionally, this alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
9.9
DANN
Benign
0.92
DEOGEN2
Benign
0.23
T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.34
T
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.093
T
MetaSVM
Benign
-0.60
T
MutationAssessor
Benign
1.5
L
PhyloP100
0.43
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.26
N
REVEL
Benign
0.22
Sift
Benign
0.26
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.037
MutPred
0.16
Loss of methylation at K120 (P = 0.0707);
MVP
0.89
MPC
0.12
ClinPred
0.40
T
GERP RS
4.7
Varity_R
0.098
gMVP
0.64
Mutation Taster
=89/11
polymorphism

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

Other links and lift over

dbSNP: rs139202426; hg19: chr21-35743134; API