21-34449497-G-T

Variant names:

• chr21-34449497-G-T
• rs758346045
• NM_000219.6:c.138C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000219.6(KCNE1):​c.138C>A​(p.Tyr46*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 999,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y46Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: KCNE1 NM_000219.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.322
• 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-34449497-G-T is Pathogenic according to our data. Variant chr21-34449497-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 547162.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.138C>A	p.Tyr46*	stop_gained	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.138C>A	p.Tyr46*	stop_gained	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251440 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000300 AC: 3 AN: 999724 Hom.: 0 Cov.: 21 AF XY: 0.00000595 AC XY: 3 AN XY: 504396

African (AFR) AF: 0.00 AC: 0 AN: 22602

American (AMR) AF: 0.00 AC: 0 AN: 38364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20862

East Asian (EAS) AF: 0.00 AC: 0 AN: 31836

South Asian (SAS) AF: 0.0000294 AC: 2 AN: 67958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00000138 AC: 1 AN: 725276

Other (OTH) AF: 0.00 AC: 0 AN: 43218

GnomAD4 genome Cov.: 14

Alfa AF: 0.0000237 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Jervell and Lange-Nielsen syndrome 2 Pathogenic:1

Jun 21, 2018

National Institute on Deafness and Communication Disorders, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Long QT syndrome Pathogenic:1

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr46*) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the KCNE1 protein. This variant is present in population databases (rs758346045, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 30461122). ClinVar contains an entry for this variant (Variation ID: 547162). This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Arg98Trp) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		0.32
Vest4		0.91
GERP RS		1.4
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs758346045; hg19: chr21-35821795;