21-34370507-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_172201.2(KCNE2):c.29C>T(p.Thr10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T10A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5 O:1
• Conservation: PhyloP100: 0.894

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE2	NM_172201.2	c.29C>T	p.Thr10Met	missense_variant	2/2	ENST00000290310.4
LOC105372791	XR_937683.3			downstream_gene_variant
LOC105372791	XR_007067848.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE2	ENST00000290310.4	c.29C>T	p.Thr10Met	missense_variant	2/2	1	NM_172201.2	P1
	ENST00000440403.2	n.782G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251330 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135878

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000226 AC: 331 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 169 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74300

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000522 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The Thr10Met variant in KCNE2 has previously been reported in 2 individuals with Long QT syndrome; however, in one family this variant was also identified in a 76 year-old relative who had coronary artery disease, congestive heart failure, and hypertension, but a normal ECG (Tester 2005, Gordon 2008). Functional studies have shown that the Thr10Met variant moderately impacts protein function (Gordon 2008); however, this in vitro assay may not accurately represent biological function. Whether KCNE2 variants alone cause Long QT syndrome or only confer increased risk when combined with other risk alleles is currently unclear. In summary, there is insufficient evidence for pathogenicity of this variant, and additional studies are needed to fully assess its clinical significance. -

Long QT syndrome 6 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are proposed mechanisms of disease in this gene and are associated with long QT syndrome 6 (MIM#613693) and familial atrial fibrillation (MIM#611493), respectively. However, this should be interpreted with caution as the gene-disease association for KCNE2 is currently unclear (PMIDs: 22166675, 26123744, 24796621, 28794082, 15368194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v2) (66 heterozygotes, 0 homozygotes) with a subpopulation frequency of 0.003 in the Ashkenazi Jewish population. (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.T10K variant has previously been reported in a patient with atrial fibrillation (PMID: 29805884). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. Although this variant has been identified in individuals with long QT syndrome and sudden unexplained death, it has more recently been re-classified as either a variant of uncertain significance or a likely benign variant (PMIDs: 18006462, 22677073, 28600387, 28794082, 32268277; ClinVar). (I) 1010 - Functional evidence for this variant is inconclusive. Patch clamp analysis in CHO cells demonstrated mild changes in the Ikr ventricular repolarization current when expressed in heterozygous state however the reliablity of this assay is questionable. Moreover, the use of CHO cells might not reflect the correct environment for testing a cardiac-related response (PMID: 18006462). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 05, 2019

Variant summary: KCNE2 c.29C>T (p.Thr10Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251330 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE2 causing Arrhythmia phenotype (7e-05), strongly suggesting that the variant is benign. c.29C>T has been reported in the literature in individuals affected with long QT syndrome and Brugada syndrome and also, in individuals with sudden unexplained deaths (e.g. Burashnikov_2010, Burns_2016, Christiansen_2016, Lieve_2013, Mellor_2017, Tester_2012). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In at least two studies presenting patients affected with long QT syndrome (Roberts_2017) and a patient affected with auditory stimulus-induced long QT syndrome (Gordon_2008), the variant was detected in affected probands but it was also detected in their asymptomatic family members and therefore, appeared to not segregate with disease. Furthermore, Gordon et al (2008) carried out functional assessment of the variant through usage of whole-cell voltage clamp of transfected Chinese Hamster ovary cells and showed baseline IKr current reduction and slower recovery from inactivation for T10M-MiRP1-hERG channels when compared with wild-type channels, however only mild changes in IKr when KCNE2-Thr10Met was co-expressed with wild-type KCNH2. At least two co-occurrences with other pathogenic variants have been reported (PKP2 c.397C>T, p.Q133* (internal testing) and KCNQ1 c.1781G>A, p.Arg594Gln (Roberts_2017)), providing supporting evidence for a benign outcome for this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and as likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy;C0023976:Long QT syndrome Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Nov 21, 2018

The KCNE2 Thr10Met variant has been previously reported in probands with Long QT syndrome (Tester DJ, et al., 2005; Gordon E, et al., 2008; Lieve KV, et al., 2013). We have identified this variant in 2 probands. The first proband is of north-west European descent, has HCM and a second likely pathogenic variant in MYL2. Our second patient is of Ashkenazi Jewish descent and has a clinical diagnosis of long QT syndrome. The variant has been identified 63 times in the Genome Aggregation Database (MAF=0.0002; http://gnomad.broadinstitute.org/) and the Ashkenazi Jewish sub-population frequency is 0.0037, which is far higher than expected based on the prevalence of LQTS. In silico tools SIFT and PolyPhen2 predict this variant to be deleterious, but MutationTaster predicts it to be a 'polymorphism'. In summary based on the high allele frequency in the general population we classify KCNE2 Thr10Met as 'benign'. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2020

This alteration is classified as likely 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. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:18006462). 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	0.10
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	0.022	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.95	P
Vest4		0.11
MVP		0.94
MPC		0.12
ClinPred		0.040	T
GERP RS		4.7
Varity_R		0.063
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473648; hg19: chr21-35742806; COSMIC: COSV51709833; COSMIC: COSV51709833;