NM_005472.5:c.248G>A

Variant names:

• chr11-74457316-C-T
• rs17215437
• NM_005472.5:c.248G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: 2.00
• Publications: 34 publications found

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000254928 (HGNC:):

ACMG classification

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

Selected	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

Ensembl Transcripts

Selected	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
	KCNE3	ENST00000525550.1	TSL:1	c.248G>A	p.Arg83His	missense	Exon 2 of 2	ENSP00000433633.1
	KCNE3	ENST00000532569.5	TSL:4	c.248G>A	p.Arg83His	missense	Exon 3 of 3	ENSP00000431739.1

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152194 Hom.: 2 Cov.: 32

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

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.: 31 Cov.: 30 AF XY: 0.00470 AC XY: 3421 AN XY: 727230

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00266 AC: 119 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00296 AC: 158 AN: 53398

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00584 AC: 6492 AN: 1111988

Other (OTH) AF: 0.00452 AC: 273 AN: 60392

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74480

African (AFR) AF: 0.00135 AC: 56 AN: 41564

American (AMR) AF: 0.00483 AC: 74 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00616 AC: 419 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00431 Hom.: 5

Bravo AF: 0.00362

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00676 AC: 58

ExAC AF: 0.00296 AC: 359

EpiCase AF: 0.00485

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Apr 01, 2007

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNE3: BS1, BS2

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: none, 11207363, 11874988, 24055113, 12414843, 14504341, 15037716, 20051516)

Jul 15, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:2 Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several pubs, including possible segs and functional studies, but frequency is too high for disease and wrong phenotype. ExAC: 0.4% (289/66352) European chromosomes

Dec 11, 2012

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNE3 p.Arg83His Based on the data reviewed below we consider it a variant of uncertain significance, probably benign. The variant has been reported in cases of periodic paralysis (Abbot et al 2001, Dias Da Silva et al 2002, Sterberg et al 2003). However, it was then later found in controls, suggesting it is likely benign and was identified in these cases because it is present in 0.1-1% of all individuals (reviewed in more detail below). Hedley et al (2011) investigated the KCNE genes as putative HCM genes. In their cohort of 93 unrelated HCM patients two individuals had p.Arg83His in KCNE3. However, the authors concluded it was not causative since one of the patients also had a presumed pathogenic TNNT2 variant (specific variant not cited) and because of the prevalence in the general population. In silico analysis with PolyPhen-2 predicts the variant to be benign. The arginine at codon 83 is not conserved across species and in the marmoset is in fact a histidine. The KCNE3 gene has been associated with Brugada syndrome type 6 (Deplon et al 2008) and periodic paralysis (Abbott et al 2001). In total the variant has not been seen with allele frequencies of 0.1-1.1% in individuals in general population samples (rs17215437). Another variant, c.248G>T has been seen with allele frequencies of 0.14-1.52% in 1000 genomes. The variant was recently reported online in 50 of 5379 individuals in the NHLBI Exome Sequencing Project dataset (as of December 11th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 01, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Brugada syndrome 6 Uncertain:1 Benign:3

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance.

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Syncope;C0042510:Ventricular fibrillation Uncertain:1

Jul 03, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Periodic paralysis Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Cardiomyopathy Benign:1

Jan 10, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

May 11, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.052	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.58
Sift	Benign	0.044	D
Sift4G	Benign	0.077	T
Polyphen		0.0030	B
Vest4		0.47
MVP		0.93
MPC		0.15
ClinPred		0.027	T
GERP RS		3.4
Varity_R		0.49
gMVP		0.88
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs17215437; hg19: chr11-74168361; COSMIC: COSV107382359; COSMIC: COSV107382359;