rs199473363

chr21-34370537-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_172201.2(KCNE2):c.59T>A(p.Ile20Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. I20I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.70

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE2	NM_172201.2	c.59T>A	p.Ile20Asn	missense_variant	2/2	ENST00000290310.4
LOC105372791	XR_937683.3	n.1317A>T		non_coding_transcript_exon_variant	2/2
LOC105372791	XR_007067848.1	n.1352A>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE2	ENST00000290310.4	c.59T>A	p.Ile20Asn	missense_variant	2/2	1	NM_172201.2	P1
	ENST00000440403.2	n.752A>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	11
Dann	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.23
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.055	B
Vest4		0.70
MutPred		0.81		Loss of sheet (P = 0.0063);
MVP		0.79
MPC		0.20
ClinPred		0.19	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs199473363; hg19: chr21-35742836;