Genetic Variant KCNE1:p.Gly55Ser (chr21-34449472-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_000219.6(KCNE1):c.163G>A(p.Gly55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,202,928 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign 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. G55V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000048 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000063 ( 4 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2O:1

Conservation

PhyloP100: 3.10

Publications

11 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: Likely_benign. The variant received -4 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, 104 uncertain in NM_000219.6

BP4

Computational evidence support a benign effect (MetaRNN=0.30607957).

BP6

Variant 21-34449472-C-T is Benign according to our data. Variant chr21-34449472-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132657.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.163G>A	p.Gly55Ser	missense	Exon 4 of 4	NP_000210.2	P15382
KCNE1	NM_001127668.4		c.163G>A	p.Gly55Ser	missense	Exon 3 of 3	NP_001121140.1	P15382
KCNE1	NM_001127669.4		c.163G>A	p.Gly55Ser	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.163G>A	p.Gly55Ser	missense	Exon 4 of 4	ENSP00000382226.2	P15382
KCNE1	ENST00000399289.7	TSL:1	c.163G>A	p.Gly55Ser	missense	Exon 3 of 3	ENSP00000382228.3	P15382
KCNE1	ENST00000416357.6	TSL:1	c.163G>A	p.Gly55Ser	missense	Exon 2 of 2	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes

AF:

0.0000482

AC:

AN:

103632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000335

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000208

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

251428

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000628

AC:

AN:

1099208

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

557970

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

25198

American (AMR)

AF:

0.0000483

AC:

AN:

41434

Ashkenazi Jewish (ASJ)

AF:

0.0000430

AC:

AN:

23262

East Asian (EAS)

AF:

0.0000830

AC:

AN:

36134

South Asian (SAS)

AF:

0.000432

AC:

AN:

76392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5142

European-Non Finnish (NFE)

AF:

0.0000328

AC:

AN:

792472

Other (OTH)

AF:

0.0000208

AC:

AN:

48140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000482

AC:

AN:

103720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50074

show subpopulations

African (AFR)

AF:

0.000113

AC:

AN:

26494

American (AMR)

AF:

0.00

AC:

AN:

10696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2384

East Asian (EAS)

AF:

0.00

AC:

AN:

3046

South Asian (SAS)

AF:

0.000336

AC:

AN:

2978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

198

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

48088

Other (OTH)

AF:

0.00

AC:

AN:

1394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.585

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000522

Hom.:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (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

0.17

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.8

PhyloP100

3.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.69

Sift

Benign

0.28

Sift4G

Benign

0.27

Polyphen

0.98

Vest4

0.43

MutPred

0.34

Gain of catalytic residue at G55 (P = 0.1848)

MVP

0.93

MPC

0.29

ClinPred

0.41

GERP RS

5.2

Varity_R

0.11

gMVP

0.64

Mutation Taster

=0/100

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over