NM_172201.2:c.23C>A

Variant names:

• chr21-34370501-C-A
• rs35759083
• NM_172201.2:c.23C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_172201.2(KCNE2):​c.23C>A​(p.Thr8Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71
• Publications: 0 publications found

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]

KCNE2 Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 6

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000225555 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172201.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE2	NM_172201.2	MANE Select	c.23C>A	p.Thr8Lys	missense	Exon 2 of 2	NP_751951.1
	LOC105372791	NR_188571.1		n.786G>T		non_coding_transcript_exon	Exon 2 of 3
	LOC105372791	NR_188572.1		n.786G>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE2	ENST00000290310.4	TSL:1 MANE Select	c.23C>A	p.Thr8Lys	missense	Exon 2 of 2	ENSP00000290310.2
	KCNE2	ENST00000715813.1		c.23C>A	p.Thr8Lys	missense	Exon 6 of 6	ENSP00000520524.1
	ENSG00000225555	ENST00000440403.2	TSL:3	n.788G>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T8K variant (also known as c.23C>A), located in coding exon 1 of the KCNE2 gene, results from a C to A substitution at nucleotide position 23. The threonine at codon 8 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.46		Gain of methylation at T8 (P = 0.005)
MVP		0.98
MPC		0.58
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.77
gMVP		1.0
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35759083; hg19: chr21-35742800;