rs1555837082

Positions:

• chr21-34370668-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The ENST00000290310.4(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. 16/21 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 ENST00000290310.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25

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 Likely_benign. Variant got -1 ACMG points.

• 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 id is 471499.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE2	NM_172201.2	c.190A>G	p.Ile64Val	missense_variant	2/2	ENST00000290310.4	NP_751951.1
LOC105372791	XR_937683.3	n.1186T>C		non_coding_transcript_exon_variant	2/2
LOC105372791	XR_007067848.1	n.1221T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4	c.190A>G	p.Ile64Val	missense_variant	2/2	1	NM_172201.2	ENSP00000290310	P1
	ENST00000440403.2	n.621T>C		non_coding_transcript_exon_variant	2/3	3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2022

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
MutationTaster	Benign	0.97	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555837082; hg19: chr21-35742967;