rs587780366

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_172107.4(KCNQ2):c.2281G>T(p.Ala761Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,527,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A761T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.59

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
neonatal encephalopathy with non-epileptic myoclonus
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neonatal-onset developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
seizures, benign familial neonatal, 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
seizures, benign familial neonatal, 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
benign familial infantile epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign familial neonatal-infantile seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign neonatal seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNQ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP2

Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 7, neonatal encephalopathy with non-epileptic myoclonus, benign familial infantile epilepsy, malignant migrating partial seizures of infancy, seizures, benign familial neonatal, 1, benign familial neonatal-infantile seizures, benign neonatal seizures, seizures, benign familial neonatal, 2, undetermined early-onset epileptic encephalopathy, neonatal-onset developmental and epileptic encephalopathy.

BP6

Variant 20-63406982-C-A is Benign according to our data. Variant chr20-63406982-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1041104.

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172107.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ2	NM_172107.4	MANE Select	c.2281G>T	p.Ala761Ser	missense	Exon 17 of 17	NP_742105.1	O43526-1
KCNQ2	NM_001382235.1		c.2335G>T	p.Ala779Ser	missense	Exon 17 of 17	NP_001369164.1	A0A9L9PXL0
KCNQ2	NM_172106.3		c.2227G>T	p.Ala743Ser	missense	Exon 16 of 16	NP_742104.1	O43526-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.2281G>T	p.Ala761Ser	missense	Exon 17 of 17	ENSP00000352035.2	O43526-1
KCNQ2	ENST00000626839.2	TSL:1	c.2227G>T	p.Ala743Ser	missense	Exon 16 of 16	ENSP00000486706.1	O43526-2
KCNQ2	ENST00000344462.8	TSL:1	c.2188G>T	p.Ala730Ser	missense	Exon 16 of 16	ENSP00000339611.4	O43526-4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000782

AC:

AN:

127898

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000209

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1375816

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

677706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31432

American (AMR)

AF:

0.00

AC:

AN:

35592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24250

East Asian (EAS)

AF:

0.00

AC:

AN:

35696

South Asian (SAS)

AF:

0.00

AC:

AN:

78602

European-Finnish (FIN)

AF:

0.0000281

AC:

AN:

35606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

1071756

Other (OTH)

AF:

0.0000174

AC:

AN:

57380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000101

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.0069

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.43

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.6

PhyloP100

3.6

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.50

REVEL

Uncertain

0.45

Sift

Benign

0.40

Sift4G

Benign

0.54

Polyphen

0.96

Vest4

0.21

MutPred

0.28

Gain of sheet (P = 0.0085)

MVP

0.67

MPC

0.63

ClinPred

0.34

GERP RS

5.0

Varity_R

0.12

gMVP

0.27

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over