11-74457316-C-T

Position:

• chr11-74457316-C-T

Variant summary

Our verdict is Benign. Variant got -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).

• 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

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]

ENSG00000254631 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 5541.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=5}. Variant chr11-74457316-C-T is described in Lovd as [Benign]. Variant chr11-74457316-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 580 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE3	NM_005472.5	c.248G>A	p.Arg83His	missense_variant	3/3	ENST00000310128.9	NP_005463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE3	ENST00000310128.9	c.248G>A	p.Arg83His	missense_variant	3/3	1	NM_005472.5	ENSP00000310557.4
KCNE3	ENST00000525550.1	c.248G>A	p.Arg83His	missense_variant	2/2	1		ENSP00000433633.1
KCNE3	ENST00000532569.5	c.248G>A	p.Arg83His	missense_variant	3/3	4		ENSP00000431739.1
ENSG00000254631	ENST00000533008.1	n.155-26861C>T		intron_variant		3

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

GnomAD3 exomes AF: 0.00300 AC: 753 AN: 251278 Hom.: 7 AF XY: 0.00286 AC XY: 388 AN XY: 135846

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 SAS exome AF: 0.000359

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

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00584

Gnomad4 OTH exome AF: 0.00452

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

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00463 Hom.: 4

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	KCNE3: BS1, BS2 -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2018	This variant is associated with the following publications: (PMID: none, 11207363, 11874988, 24055113, 12414843, 14504341, 15037716, 20051516) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 15, 2020	- -

not specified Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 11, 2012	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Brugada syndrome 6 Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -

Syncope;C0042510:Ventricular fibrillation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 03, 2014

- -

Periodic paralysis Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 10, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2018

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 v4.3

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;D;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Uncertain	0.052	D
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.077	T;T;.
Polyphen		0.0030	B;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

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

LitVar

Other links and lift over

dbSNP: rs17215437; hg19: chr11-74168361;