rs199473362

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000219.6(KCNE1):c.292C>T(p.Arg98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,588,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 2.58

Publications

22 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

PP5

Variant 21-34449343-G-A is Pathogenic according to our data. Variant chr21-34449343-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132676.

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.292C>T	p.Arg98Trp	missense	Exon 4 of 4	NP_000210.2	P15382
KCNE1	NM_001127668.4		c.292C>T	p.Arg98Trp	missense	Exon 3 of 3	NP_001121140.1	P15382
KCNE1	NM_001127669.4		c.292C>T	p.Arg98Trp	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.292C>T	p.Arg98Trp	missense	Exon 4 of 4	ENSP00000382226.2	P15382
KCNE1	ENST00000399289.7	TSL:1	c.292C>T	p.Arg98Trp	missense	Exon 3 of 3	ENSP00000382228.3	P15382
KCNE1	ENST00000416357.6	TSL:1	c.292C>T	p.Arg98Trp	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes

AF:

0.00000708

AC:

AN:

141302

Hom.:

Cov.:

show subpopulations

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:

0.000236

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251432

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000470

AC:

AN:

1447288

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

AN XY:

720798

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33338

American (AMR)

AF:

0.0000224

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.000101

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000419

AC:

AN:

1098392

Other (OTH)

AF:

0.0000167

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.00000708

AC:

AN:

141302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38702

American (AMR)

AF:

0.00

AC:

AN:

13916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3250

East Asian (EAS)

AF:

0.00

AC:

AN:

4606

South Asian (SAS)

AF:

0.000236

AC:

AN:

4232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63872

Other (OTH)

AF:

0.00

AC:

AN:

1894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (2)

not provided (2)

Cardiovascular phenotype (1)

Long QT syndrome 5 (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

PhyloP100

2.6

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.52

MVP

0.93

MPC

0.44

ClinPred

0.80

GERP RS

4.0

Varity_R

0.24

gMVP

0.76

Mutation Taster

=0/100

disease causing (ClinVar)

(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