21-34511314-T-C

Position:

chr21-34511314-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000219.6(KCNE1):c.-375A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 985,560 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 66 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 35 hom. )

Consequence

KCNE1
NM_000219.6 splice_region

Scores

Splicing: ADA: 0.0002495

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.243

Variant links:

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 links:

ENSG00000288711 (HGNC:):

ENSG00000288711 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 21-34511314-T-C is Benign according to our data. Variant chr21-34511314-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 339782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.-375A>G		splice_region_variant	2/4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6
KCNE1	NM_000219.6 linkuse as main transcript	c.-375A>G		5_prime_UTR_variant	2/4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.-375A>G	splice_region_variant	2/4	1	NM_000219.6	ENSP00000382226.2	P15382
KCNE1	ENST00000399286.3 linkuse as main transcript	c.-375A>G	5_prime_UTR_variant	2/4	1	NM_000219.6	ENSP00000382226.2	P15382
ENSG00000288711	ENST00000684114.1 linkuse as main transcript	n.*171A>G	splice_region_variant, non_coding_transcript_exon_variant	5/5			ENSP00000507841.1	A0A804HKA1
ENSG00000288711	ENST00000684114.1 linkuse as main transcript	n.*171A>G	3_prime_UTR_variant	5/5			ENSP00000507841.1	A0A804HKA1

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2496

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0573

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0139

GnomAD4 exome

AF:

0.00142

AC:

1181

AN:

833232

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

493

AN XY:

384808

show subpopulations

Gnomad4 AFR exome

AF:

0.0642

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000932

Gnomad4 OTH exome

AF:

0.00315

GnomAD4 genome

AF:

0.0164

AC:

2495

AN:

152328

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1156

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0571

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0205

Hom.:

Bravo

AF:

0.0185

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Congenital long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Jervell and Lange-Nielsen syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.5

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.042

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over