11-74457316-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005472.5(KCNE3):c.248G>A(p.Arg83His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,148 control chromosomes in the GnomAD database, including 33 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. R83C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 31 hom. )

Consequence

KCNE3
NM_005472.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:12

Conservation

PhyloP100: 2.00

Publications

34 publications found

Variant links:

Genes affected

KCNE3 (HGNC:6243): (potassium voltage-gated channel subfamily E regulatory subunit 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the kidney. A missense mutation in this gene is associated with hypokalemic periodic paralysis. [provided by RefSeq, Jul 2008]

KCNE3 Gene-Disease associations (from GenCC):

Brugada syndrome 6
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Brugada syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNE3 links:

ENSG00000254928 (HGNC:):

ENSG00000254928 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012397826).

BP6

Variant 11-74457316-C-T is Benign according to our data. Variant chr11-74457316-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5541.

BS2

High AC in GnomAd4 at 580 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005472.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE3	NM_005472.5	MANE Select	c.248G>A	p.Arg83His	missense	Exon 3 of 3	NP_005463.1	Q9Y6H6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNE3	ENST00000310128.9	TSL:1 MANE Select	c.248G>A	p.Arg83His	missense	Exon 3 of 3	ENSP00000310557.4	Q9Y6H6
KCNE3	ENST00000525550.1	TSL:1	c.248G>A	p.Arg83His	missense	Exon 2 of 2	ENSP00000433633.1	Q9Y6H6
KCNE3	ENST00000875764.1		c.248G>A	p.Arg83His	missense	Exon 4 of 4	ENSP00000545823.1

Frequencies

GnomAD3 genomes

AF:

0.00381

AC:

580

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00616

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00300

AC:

753

AN:

251278

AF XY:

0.00286

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.00491

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00487

AC:

7112

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

3421

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00266

AC:

119

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00296

AC:

158

AN:

53398

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00584

AC:

6492

AN:

1111988

Other (OTH)

AF:

0.00452

AC:

273

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

391

781

1172

1562

1953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.00381

AC:

580

AN:

152312

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41564

American (AMR)

AF:

0.00483

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00616

AC:

419

AN:

68022

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

122

152

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:

0.00431

Hom.:

Bravo

AF:

0.00362

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00676

AC:

ExAC

AF:

0.00296

AC:

359

EpiCase

AF:

0.00485

EpiControl

AF:

0.00409

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Brugada syndrome 6 (4)

not specified (4)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (1)

Periodic paralysis (1)

Syncope;C0042510:Ventricular fibrillation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.88

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.71

M_CAP

Benign

0.035

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.052

MutationAssessor

Uncertain

2.2

PhyloP100

2.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.58

Sift

Benign

0.044

Sift4G

Benign

0.077

Polyphen

0.0030

Vest4

0.47

MVP

0.93

MPC

0.15

ClinPred

0.027

GERP RS

3.4

Varity_R

0.49

gMVP

0.88

Mutation Taster

=84/16

polymorphism

(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

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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