NM_000219.6:c.162C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3

The NM_000219.6(KCNE1):​c.162C>A​(p.Phe54Leu) 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 not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F54C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 16)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

7
7
5

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -1.17
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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, 17 uncertain in NM_000219.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-34449475-A-C is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNE1NM_000219.6 linkc.162C>A p.Phe54Leu missense_variant Exon 4 of 4 ENST00000399286.3 NP_000210.2 P15382C7S316Q6FHJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNE1ENST00000399286.3 linkc.162C>A p.Phe54Leu missense_variant Exon 4 of 4 1 NM_000219.6 ENSP00000382226.2 P15382

Frequencies

GnomAD3 genomes
Cov.:
16
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1100726
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
558660
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.:
16

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Long QT syndrome 5 Other:1
-
Roden Lab, Vanderbilt University Medical Center
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.31
CADD
Benign
0.055
DANN
Uncertain
0.97
DEOGEN2
Pathogenic
0.96
D;D;D;D;D;D;D;D
Eigen
Benign
-0.90
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.75
.;.;T;.;.;.;.;.
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Uncertain
2.8
M;M;M;M;M;M;M;M
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-4.8
D;.;.;D;D;D;D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0050
D;.;.;D;D;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D;D;D;D;D
Polyphen
0.99
D;D;D;D;D;D;D;D
Vest4
0.85
MutPred
0.34
Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);Loss of catalytic residue at F54 (P = 0.1671);
MVP
0.80
MPC
0.44
ClinPred
0.99
D
GERP RS
-6.2
Varity_R
0.59
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-35821771; API