rs2834502

Variant names:

• chr21-34511191-C-T
• rs2834502
• ENST00000684114.1:n.*294G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000684114.1(ENSG00000288711):​n.*294G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 985,406 control chromosomes in the GnomAD database, including 27,164 homozygotes. 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 0.21 (4172 hom., cov: 32)
  • Exomes 𝑓: 0.23 (22992 hom.)
• Consequence: ENSG00000288711 ENST00000684114.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.268
• Publications: 8 publications found

Genes affected

ENSG00000288711 (HGNC:):

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.-252G>A		5_prime_UTR_variant	Exon 2 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000288711	ENST00000684114.1	n.*294G>A		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000507841.1
KCNE1	ENST00000399286.3	c.-252G>A		5_prime_UTR_variant	Exon 2 of 4	1	NM_000219.6	ENSP00000382226.2
ENSG00000288711	ENST00000684114.1	n.*294G>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000507841.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31417 AN: 152088 Hom.: 4170 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.232 AC: 193398 AN: 833200 Hom.: 22992 Cov.: 30 AF XY: 0.231 AC XY: 88942 AN XY: 384860

African (AFR) AF: 0.0377 AC: 596 AN: 15796

American (AMR) AF: 0.367 AC: 361 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 1269 AN: 5152

East Asian (EAS) AF: 0.504 AC: 1835 AN: 3642

South Asian (SAS) AF: 0.176 AC: 2896 AN: 16464

European-Finnish (FIN) AF: 0.241 AC: 67 AN: 278

Middle Eastern (MID) AF: 0.225 AC: 366 AN: 1624

European-Non Finnish (NFE) AF: 0.235 AC: 179331 AN: 761950

Other (OTH) AF: 0.244 AC: 6677 AN: 27310

GnomAD4 genome AF: 0.206 AC: 31420 AN: 152206 Hom.: 4172 Cov.: 32 AF XY: 0.211 AC XY: 15691 AN XY: 74410

African (AFR) AF: 0.0575 AC: 2389 AN: 41566

American (AMR) AF: 0.329 AC: 5034 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 838 AN: 3470

East Asian (EAS) AF: 0.520 AC: 2684 AN: 5166

South Asian (SAS) AF: 0.199 AC: 957 AN: 4816

European-Finnish (FIN) AF: 0.238 AC: 2521 AN: 10592

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.239 AC: 16265 AN: 67980

Other (OTH) AF: 0.229 AC: 483 AN: 2110

Alfa AF: 0.235 Hom.: 13239

Bravo AF: 0.214

Asia WGS AF: 0.329 AC: 1140 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Long QT syndrome 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital long QT syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jervell and Lange-Nielsen syndrome 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.7
DANN	Benign	0.66
PhyloP100		0.27
PromoterAI		-0.0067	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2834502; hg19: chr21-35883489;