ENST00000684114.1:n.*293A>G

Variant names:

• chr21-34511192-T-C
• rs41315471
• ENST00000684114.1:n.*293A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000684114.1(ENSG00000288711):​n.*293A>G 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 0.00661 in 985,752 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (127 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (75 hom.)
• Consequence: ENSG00000288711 ENST00000684114.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.244
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 21-34511192-T-C is Benign according to our data. Variant chr21-34511192-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 339780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.-253A>G		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.*293A>G		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000507841.1
KCNE1	ENST00000399286.3	c.-253A>G		5_prime_UTR_variant	Exon 2 of 4	1	NM_000219.6	ENSP00000382226.2
ENSG00000288711	ENST00000684114.1	n.*293A>G		3_prime_UTR_variant	Exon 5 of 5			ENSP00000507841.1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3787 AN: 152174 Hom.: 126 Cov.: 33

Gnomad AFR AF: 0.0731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00326 AC: 2718 AN: 833460 Hom.: 75 Cov.: 30 AF XY: 0.00317 AC XY: 1220 AN XY: 384966

African (AFR) AF: 0.0821 AC: 1297 AN: 15792

American (AMR) AF: 0.00610 AC: 6 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5156

East Asian (EAS) AF: 0.0519 AC: 189 AN: 3642

South Asian (SAS) AF: 0.0428 AC: 705 AN: 16466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 278

Middle Eastern (MID) AF: 0.00985 AC: 16 AN: 1624

European-Non Finnish (NFE) AF: 0.000255 AC: 194 AN: 762200

Other (OTH) AF: 0.0114 AC: 311 AN: 27318

GnomAD4 genome AF: 0.0249 AC: 3799 AN: 152292 Hom.: 127 Cov.: 33 AF XY: 0.0256 AC XY: 1906 AN XY: 74462

African (AFR) AF: 0.0732 AC: 3042 AN: 41566

American (AMR) AF: 0.0127 AC: 194 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0448 AC: 232 AN: 5182

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68016

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0323 Hom.: 73

Bravo AF: 0.0275

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign/Likely 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: Likely 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. -

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. -

Congenital long QT syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.9
DANN	Benign	0.61
PhyloP100		0.24
PromoterAI		-0.0032	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41315471; hg19: chr21-35883490;