rs3746366

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_172107.4(KCNQ2):c.2264A>G(p.Tyr755Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,539,978 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y755Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 2 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 2.87

Variant links:

Genes affected

KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNQ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, KCNQ2

BP4

Computational evidence support a benign effect (MetaRNN=0.009446293).

BP6

Variant 20-63406999-T-C is Benign according to our data. Variant chr20-63406999-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000933 (142/152274) while in subpopulation EAS AF= 0.00853 (44/5156). AF 95% confidence interval is 0.00653. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.2264A>G	p.Tyr755Cys	missense_variant	17/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7 linkuse as main transcript	c.2264A>G	p.Tyr755Cys	missense_variant	17/17	1	NM_172107.4	A1	O43526-1

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00536

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00851

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00333

AC:

490

AN:

147114

Hom.:

AF XY:

0.00247

AC XY:

201

AN XY:

81352

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0103

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000512

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.000531

AC:

737

AN:

1387704

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

306

AN XY:

684476

show subpopulations

Gnomad4 AFR exome

AF:

0.0000630

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00681

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000158

Gnomad4 OTH exome

AF:

0.000329

GnomAD4 genome

AF:

0.000933

AC:

142

AN:

152274

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00529

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00853

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.00170

ExAC

AF:

0.00105

AC:

117

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2017	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

This alteration is classified as 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. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 03, 2020

This variant is associated with the following publications: (PMID: 31152295, 32276107, 31199083, 21685056) -

Complex neurodevelopmental disorder

Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.060

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

MetaRNN

Benign

0.0094

T;T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationTaster

Benign

0.82

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.69

Sift4G

Benign

0.11

T;.;T;T;T;T

Polyphen

1.0

D;.;D;.;D;D

Vest4

0.20

MVP

0.83

MPC

0.79

ClinPred

0.071

GERP RS

2.8

Varity_R

0.19

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over