21-34364156-G-A

Position:

• chr21-34364156-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_172201.2(KCNE2):​c.-13+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000401 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE2 NM_172201.2 splice_region, intron
• Scores: Splicing: ADA: 0.9934
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 4.09

Genes affected

KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]

ENSG00000225555 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE2	NM_172201.2	c.-13+5G>A		splice_region_variant, intron_variant		ENST00000290310.4	NP_751951.1
LOC105372791	NR_188571.1	n.852+6279C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4	c.-13+5G>A		splice_region_variant, intron_variant		1	NM_172201.2	ENSP00000290310.2
ENSG00000225555	ENST00000440403.2	n.854+6279C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	The c.-13+5 G>A variant of uncertain significance in the 5'UTR of the KCNE2 gene has been reported in two unrelated individuals tested for LQTS at GeneDx and was absent from 200 Caucasian and 100 African American healthy control individuals (Lieve et al., 2013). One of these individuals also harbored a variant in the KCNH2 gene that was expected to contribute to disease (Lieve et al., 2013). The c.-13+5 G>A variant has also been identified in several additional individuals referred for arrhythmia testing at GeneDx, however familial segregation information was either unavailable or uninformative. Additional data from large control populations were not sufficient to assess whether c.-13+5 G>A may be a common benign variant in the general population (Lek et al., 2016). This single nucleotide substitution occurs in the splice donor site of intron 1, and exon 1 is a non-coding exon. In addition, the guanine (G) is conserved at this position across vertebrate species. In silico analysis using two different splice algorithms predicts that this variant significantly reduces the quality of this splice site, while a third algorithm showed only a modest change. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. In addition, no other splice site variants in the KCNE2 gene have been reported in the Human Gene Mutation Database in association with KCNE2-related disorders (Stenson et al., 2014) and the majority of pathogenic variants in the KCNE2 gene are missense changes, indicating haploinsufficiency may not be sufficient to cause disease. -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 04, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2022	The KCNE2 c.-13+5G>A variant (rs786205806) is reported in the literature in individuals affected with long QT syndrome (Lieve 2013), but at least one individual has another molecular explanation for disease (Roberts 2017). This variant is also reported in ClinVar (Variation ID: 190793), and is found in the general population with an allele frequency of 0.013% (4/31398 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing weakening the nearby canonical donor splice site. However, this splice site is in a non-coding exon, and variants affecting splicing in KCNE2 have not been reported in association with disease. Thus, without functional studies the effect on splicing is unknown. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. PMID: 23631430. Roberts JD et al. Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation? Circ Arrhythm Electrophysiol. 2017 Aug;10(8):e005282. PMID: 28794082. -

Long QT syndrome 6 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2022	This variant occurs in a non-coding region of the KCNE2 gene. It does not change the encoded amino acid sequence of the KCNE2 protein. This variant is present in population databases (rs786205806, gnomAD 1.0%). This variant has been observed in individual(s) with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 190793). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Atrial fibrillation, familial, 4;C3150953:Long QT syndrome 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Atrial fibrillation, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205806; hg19: chr21-35736455;