Genetic Variant KCNE1:p.Phe54Leu (chr21-34449473-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP3

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 (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

Clinical Significance

- - O:1

Conservation

PhyloP100: -1.17

Publications

0 publications found

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]

KCNE1 Gene-Disease associations (from GenCC):

long QT syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Jervell and Lange-Nielsen syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 101 uncertain in NM_000219.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.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
KCNE1	ENST00000399286.3 link	c.162C>A	p.Phe54Leu	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1100726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

558660

African (AFR)

AF:

0.00

AC:

AN:

25218

American (AMR)

AF:

0.00

AC:

AN:

41462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23262

East Asian (EAS)

AF:

0.00

AC:

AN:

36132

South Asian (SAS)

AF:

0.00

AC:

AN:

76444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5150

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

793892

Other (OTH)

AF:

0.00

AC:

AN:

48156

GnomAD4 genome

Cov.:

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

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

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

0.055

(source)

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

LIST_S2

Benign

0.75

.;.;T;.;.;.;.;.

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M;M

PhyloP100

-1.2

PrimateAI

Uncertain

0.72

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

GERP RS

-6.2

Varity_R

0.36

gMVP

0.83

Mutation Taster

=30/70

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over