rs1555837082

Variant names:

• chr21-34370668-A-G
• rs1555837082
• NM_172201.2:c.190A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_172201.2(KCNE2):​c.190A>G​(p.Ile64Val) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I64I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25
• 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 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_172201.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1782181).
• BP6: Variant 21-34370668-A-G is Benign according to our data. Variant chr21-34370668-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471499.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE2	NM_172201.2	c.190A>G	p.Ile64Val	missense_variant	Exon 2 of 2	ENST00000290310.4	NP_751951.1
LOC105372791	NR_188571.1	n.619T>C		non_coding_transcript_exon_variant	Exon 2 of 3
LOC105372791	NR_188572.1	n.619T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4	c.190A>G	p.Ile64Val	missense_variant	Exon 2 of 2	1	NM_172201.2	ENSP00000290310.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 6 Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with valine at codon 64 of the KCNE2 protein (p.Ile64Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with KCNE2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiovascular phenotype Benign:1

Aug 31, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.12
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.098
MutPred		0.28		Gain of catalytic residue at I64 (P = 0.0062);
MVP		0.72
MPC		0.093
ClinPred		0.61	D
GERP RS		2.1
Varity_R		0.051
gMVP		0.54
Mutation Taster		=82/18	polymorphism

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: rs1555837082; hg19: chr21-35742967;