21-34370557-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_172201.2(KCNE2):c.79C>T(p.Arg27Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,062 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. R27H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3B:2O:1

Conservation

PhyloP100: 1.70

Publications

24 publications found

Variant links:

Genes affected

KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 2) 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 small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]

KCNE2 Gene-Disease associations (from GenCC):

familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
long QT syndrome 6
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNE2 links:

ENSG00000225555 (HGNC:):

ENSG00000225555 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNE2	NM_172201.2 link	c.79C>T	p.Arg27Cys	missense_variant	Exon 2 of 2	ENST00000290310.4	NP_751951.1
LOC105372791	NR_188571.1 link	n.730G>A		non_coding_transcript_exon_variant	Exon 2 of 3
LOC105372791	NR_188572.1 link	n.730G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4 link	c.79C>T	p.Arg27Cys	missense_variant	Exon 2 of 2	1	NM_172201.2	ENSP00000290310.2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

251466

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112008

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000591

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000962

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.553

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:

0.0000520

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KCNE2 c.79C>T; p.Arg27Cys variant (rs74315449, ClinVar variant ID 6055) was detected in two Chinese patients with atrial fibrillation (Yang 2004) and was also one of two KCNE2 variants present in a child with long QT syndrome (Sauer 2016). Relatives of the Chinese patients who also carried the variant had mild cardiac symptoms, making it unclear whether or not the variant segregated with disease in these families (Yang 2004). Functional studies of this variant in cell lines were consistent with it being a gain-of-function variant; other gain-of-function variants in KCNE2 are associated with atrial fibrillation and short QT syndrome, while loss-of-function variants are more often associated with long QT syndrome (Yang 2004, Liu 2014). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.01% (identified on 37 out of 277,220 chromosomes). The arginine at position 27 is highly conserved, considering 11 species, and computational analyses of the effects of the p.Arg27Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Arg27Cys variant cannot be determined with certainty. -

Jan 13, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in an individual with left ventricular non-compaction (LVNC) who also harbored a pathogenic variant in the TNNT2 gene (PMID: 31918855); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28794082, 15368194, 16487223, 28518168, 31521807, 22947121, 24681347, 31918855) -

Atrial fibrillation, familial, 4;C3150953:Long QT syndrome 6

Pathogenic:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Atrial fibrillation, familial, 4

Pathogenic:1

Nov 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Long QT syndrome;C0949658:Primary familial hypertrophic cardiomyopathy

Uncertain:1

Nov 04, 2014

Blueprint Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 08, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Long QT syndrome 6

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial fibrillation

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:15368194;PMID:16487223). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.86

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.4

PhyloP100

1.7

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.63

MutPred

0.83

Loss of disorder (P = 0.0206);

MVP

0.96

MPC

0.58

ClinPred

0.54

GERP RS

4.6

Varity_R

0.32

gMVP

0.91

Mutation Taster

=32/68

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over