Genetic Variant NM_172107.4:c.2238T>A (chr20-63407025-A-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_172107.4(KCNQ2):c.2238T>A(p.Pro746Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0944 in 1,522,048 control chromosomes in the GnomAD database, including 7,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 587 hom., cov: 33)

Exomes 𝑓: 0.096 ( 7189 hom. )

Consequence

KCNQ2
NM_172107.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.933

Publications

10 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
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
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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 20-63407025-A-T is Benign according to our data. Variant chr20-63407025-A-T is described in ClinVar as Benign. ClinVar VariationId is 129342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.933 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

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
KCNQ2	NM_172107.4	MANE Select	c.2238T>A	p.Pro746Pro	synonymous	Exon 17 of 17	NP_742105.1
KCNQ2	NM_001382235.1		c.2292T>A	p.Pro764Pro	synonymous	Exon 17 of 17	NP_001369164.1
KCNQ2	NM_172106.3		c.2184T>A	p.Pro728Pro	synonymous	Exon 16 of 16	NP_742104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.2238T>A	p.Pro746Pro	synonymous	Exon 17 of 17	ENSP00000352035.2
KCNQ2	ENST00000626839.2	TSL:1	c.2184T>A	p.Pro728Pro	synonymous	Exon 16 of 16	ENSP00000486706.1
KCNQ2	ENST00000344462.8	TSL:1	c.2145T>A	p.Pro715Pro	synonymous	Exon 16 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes

AF:

0.0759

AC:

11555

AN:

152174

Hom.:

586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0699

Gnomad ASJ

AF:

0.0507

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.0977

Gnomad MID

AF:

0.0987

Gnomad NFE

AF:

0.0990

Gnomad OTH

AF:

0.0588

GnomAD2 exomes

AF:

0.108

AC:

14010

AN:

130086

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.0490

Gnomad EAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.0959

Gnomad OTH exome

AF:

0.0980

GnomAD4 exome

AF:

0.0965

AC:

132155

AN:

1369756

Hom.:

7189

Cov.:

AF XY:

0.0991

AC XY:

66784

AN XY:

673660

show subpopulations

African (AFR)

AF:

0.0129

AC:

405

AN:

31352

American (AMR)

AF:

0.0948

AC:

3258

AN:

34372

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

1124

AN:

23926

East Asian (EAS)

AF:

0.115

AC:

4133

AN:

35990

South Asian (SAS)

AF:

0.187

AC:

14457

AN:

77324

European-Finnish (FIN)

AF:

0.104

AC:

3653

AN:

35012

Middle Eastern (MID)

AF:

0.0691

AC:

370

AN:

5352

European-Non Finnish (NFE)

AF:

0.0932

AC:

99629

AN:

1069480

Other (OTH)

AF:

0.0900

AC:

5126

AN:

56948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

7681

15362

23042

30723

38404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3664

7328

10992

14656

18320

<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:

0.0760

AC:

11567

AN:

152292

Hom.:

587

Cov.:

AF XY:

0.0780

AC XY:

5807

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0178

AC:

742

AN:

41582

American (AMR)

AF:

0.0696

AC:

1066

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

176

AN:

3472

East Asian (EAS)

AF:

0.119

AC:

613

AN:

5164

South Asian (SAS)

AF:

0.211

AC:

1018

AN:

4834

European-Finnish (FIN)

AF:

0.0977

AC:

1038

AN:

10626

Middle Eastern (MID)

AF:

0.0959

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0990

AC:

6734

AN:

67988

Other (OTH)

AF:

0.0591

AC:

125

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

553

1106

1659

2212

2765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0871

Hom.:

139

Bravo

AF:

0.0661

Asia WGS

AF:

0.176

AC:

610

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 23. Only high quality variants are reported.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 17, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Seizures, benign familial neonatal, 1

Benign:2

Apr 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Feb 05, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Developmental and epileptic encephalopathy, 7

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.3

(source)

DANN

Benign

0.73

PhyloP100

-0.93

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over