rs2234916

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_172201.2(KCNE2):c.22A>G(p.Thr8Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,180 control chromosomes in the GnomAD database, including 42 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. T8I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 38 hom. )

Consequence

KCNE2
NM_172201.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 7.93

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031698614).

BP6

Variant 21-34370500-A-G is Benign according to our data. Variant chr21-34370500-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67615.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=6, Uncertain_significance=1, Likely_benign=2}. Variant chr21-34370500-A-G is described in Lovd as [Benign]. Variant chr21-34370500-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 582 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNE2	NM_172201.2 linkuse as main transcript	c.22A>G	p.Thr8Ala	missense_variant	2/2	ENST00000290310.4
LOC105372791	XR_937683.3 linkuse as main transcript			downstream_gene_variant
LOC105372791	XR_007067848.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE2	ENST00000290310.4 linkuse as main transcript	c.22A>G	p.Thr8Ala	missense_variant	2/2	1	NM_172201.2	P1
	ENST00000440403.2 linkuse as main transcript	n.789T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

582

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00651

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00372

AC:

935

AN:

251318

Hom.:

AF XY:

0.00384

AC XY:

522

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.00602

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00563

AC:

8235

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

3995

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00311

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000812

Gnomad4 FIN exome

AF:

0.00423

Gnomad4 NFE exome

AF:

0.00659

Gnomad4 OTH exome

AF:

0.00573

GnomAD4 genome

AF:

0.00382

AC:

581

AN:

152292

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.00651

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00533

Hom.:

Bravo

AF:

0.00367

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00380

AC:

461

EpiCase

AF:

0.00583

EpiControl

AF:

0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	KCNE2: BS2 -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:10984545;PMID:11468227;PMID:12402336;PMID:14661677;PMID:14760488;PMID:15599693;PMID:17161064;PMID:17210839). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -

Long QT syndrome 6

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Long QT syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PP3, BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2011

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2015

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, drug-associated

Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Pathogenic

0.31

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.032

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MVP

0.97

MPC

0.52

ClinPred

0.037

GERP RS

5.5

Varity_R

0.53

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over