rs191334763

Variant names:

• chr21-34449639-G-T
• rs191334763
• NM_000219.6:c.-5C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000219.6(KCNE1):​c.-5C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., cov: 13)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.675
• Publications: 1 publications found

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KCNE1 Gene-Disease associations (from GenCC):

• long QT syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.-5C>A		5_prime_UTR_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.-5C>A		5_prime_UTR_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 6 AN: 96352 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250842 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000925

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000192 AC: 14 AN: 728066 Hom.: 0 Cov.: 10 AF XY: 0.0000160 AC XY: 6 AN XY: 375730

African (AFR) AF: 0.00 AC: 0 AN: 17918

American (AMR) AF: 0.00 AC: 0 AN: 32666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17894

East Asian (EAS) AF: 0.000398 AC: 13 AN: 32636

South Asian (SAS) AF: 0.00 AC: 0 AN: 60820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3368

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 487114

Other (OTH) AF: 0.0000282 AC: 1 AN: 35442

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000622 AC: 6 AN: 96448 Hom.: 0 Cov.: 13 AF XY: 0.0000860 AC XY: 4 AN XY: 46504

African (AFR) AF: 0.00 AC: 0 AN: 24320

American (AMR) AF: 0.00 AC: 0 AN: 10244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2142

East Asian (EAS) AF: 0.00212 AC: 6 AN: 2832

South Asian (SAS) AF: 0.00 AC: 0 AN: 2870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44274

Other (OTH) AF: 0.00 AC: 0 AN: 1318

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Sep 14, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-5C>A variant in KCNE1 has not been previously reported in individuals wit h arrhythmia or hearing loss, but has been identified in 0.1% (19/18862) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs191334763).This variant is located in the 5' UTR and is part of the translation initiation (Kozak) sequence, but its effect on translat ion is unknown. In summary, the clinical significance of the c.-5C>A variant is uncertain. -

May 22, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNE1 c.-5C>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 6.8e-05 in 250842 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 446.4 fold of the estimated maximal estimated allele frequency for a pathogenic variant in KCNE1 causing Long QT Syndrome phenotype (2.1e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.-5C>A has been reported in the literature in at least one individual affected with atrioventricular nodal reentry tachycardia, however without strong evidence for causality (e.g., Luo_2020). This report therefore does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 32508047). Four ClinVar submitters (evaluation after 2014) have cited with conflicting assessments: two submitters classified the variant as likely benign, and two submitters classified the variant as VUS. Based on the evidence outlined above, the variant was classified as benign. -

not provided Uncertain:1 Benign:1

Jul 27, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 5 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype Benign:1

May 25, 2021

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.82
PhyloP100		0.68
Varity_R		0.12
Mutation Taster		=294/6	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: rs191334763; hg19: chr21-35821937; COSMIC: COSV100492422;