Genetic Variant NM_172201.2:c.190A>G (chr21-34370668-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.25

Publications

0 publications found

Variant links:

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

KCNE2 links:

ENSG00000225555 (HGNC:):

ENSG00000225555 links:

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ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNE2	NM_172201.2	MANE Select	c.190A>G	p.Ile64Val	missense	Exon 2 of 2	NP_751951.1	Q9Y6J6
LOC105372791	NR_188571.1		n.619T>C		non_coding_transcript_exon	Exon 2 of 3
LOC105372791	NR_188572.1		n.619T>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNE2	ENST00000290310.4	TSL:1 MANE Select	c.190A>G	p.Ile64Val	missense	Exon 2 of 2	ENSP00000290310.2	Q9Y6J6
KCNE2	ENST00000715813.1		c.190A>G	p.Ile64Val	missense	Exon 6 of 6	ENSP00000520524.1	Q9Y6J6
ENSG00000225555	ENST00000440403.2	TSL:3	n.621T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Long QT syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.40

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.69

M_CAP

Benign

0.028

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-0.34

PhyloP100

1.2

PrimateAI

Benign

0.38

PROVEAN

Benign

0.47

REVEL

Benign

0.12

Sift

Benign

0.36

Sift4G

Benign

0.35

Polyphen

0.0010

Vest4

0.098

MutPred

0.28

Gain of catalytic residue at I64 (P = 0.0062)

MVP

0.72

MPC

0.093

ClinPred

0.61

GERP RS

2.1

Varity_R

0.051

gMVP

0.54

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over