rs199473350

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000219.6(KCNE1):c.83C>T(p.Ser28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 892,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. S28W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 12)

Exomes 𝑓: 0.0000056 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 2.53

Publications

12 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
Jervell and Lange-Nielsen syndrome 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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 mutagenesis_site No measurable effect on assembly with KCNQ1 or cell surface expression of the KCNE1/KCNQ1 channel complex, and loss of glycosylation at N-5; when associated with Q-5. 50% reduction of cell surface expression of the KCNE1/KCNQ1 channel complex, and loss of glycosylation at N-5 and T-7; when associated with A-7. (size 0) in uniprot entity KCNE1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3878041).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000219.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNE1	NM_000219.6	MANE Select	c.83C>T	p.Ser28Leu	missense	Exon 4 of 4	NP_000210.2	P15382
KCNE1	NM_001127668.4		c.83C>T	p.Ser28Leu	missense	Exon 3 of 3	NP_001121140.1	P15382
KCNE1	NM_001127669.4		c.83C>T	p.Ser28Leu	missense	Exon 3 of 3	NP_001121141.1	C7S316

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.83C>T	p.Ser28Leu	missense	Exon 4 of 4	ENSP00000382226.2	P15382
KCNE1	ENST00000399289.7	TSL:1	c.83C>T	p.Ser28Leu	missense	Exon 3 of 3	ENSP00000382228.3	P15382
KCNE1	ENST00000416357.6	TSL:1	c.83C>T	p.Ser28Leu	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

81276

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251290

AF XY:

0.0000515

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:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000560

AC:

AN:

892140

Hom.:

Cov.:

AF XY:

0.00000898

AC XY:

AN XY:

445266

show subpopulations

African (AFR)

AF:

0.0000531

AC:

AN:

18844

American (AMR)

AF:

0.00

AC:

AN:

33084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16058

East Asian (EAS)

AF:

0.00

AC:

AN:

23342

South Asian (SAS)

AF:

0.0000187

AC:

AN:

53436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3672

European-Non Finnish (NFE)

AF:

0.00000448

AC:

AN:

669040

Other (OTH)

AF:

0.00

AC:

AN:

37054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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

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

AF:

0.00

AC:

AN:

81276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

39638

African (AFR)

AF:

0.00

AC:

AN:

18960

American (AMR)

AF:

0.00

AC:

AN:

8970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1760

East Asian (EAS)

AF:

0.00

AC:

AN:

2240

South Asian (SAS)

AF:

0.00

AC:

AN:

2364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

170

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

38554

Other (OTH)

AF:

0.00

AC:

AN:

1110

Alfa

AF:

0.0000569

Hom.:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

Long QT syndrome (1)

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.091

MutationAssessor

Uncertain

2.5

PhyloP100

2.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.61

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.012

Polyphen

0.71

Vest4

0.31

MVP

0.87

MPC

0.25

ClinPred

0.82

GERP RS

3.5

Varity_R

0.10

gMVP

0.57

Mutation Taster

=2/98

disease causing

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over