Genetic Variant NM_172107.4:c.*4G>A (chr20-63406640-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172107.4(KCNQ2):c.*4G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,587,226 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 5 hom. )

Consequence

KCNQ2
NM_172107.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.27

Publications

2 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 20-63406640-C-T is Benign according to our data. Variant chr20-63406640-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00203 (309/152260) while in subpopulation NFE AF = 0.00348 (237/68012). AF 95% confidence interval is 0.00312. There are 0 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 309 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	Effect	Exon Rank	Protein	UniProt
KCNQ2	NM_172107.4	MANE Select	c.*4G>A	3_prime_UTR	Exon 17 of 17	NP_742105.1	O43526-1
KCNQ2	NM_001382235.1		c.*4G>A	3_prime_UTR	Exon 17 of 17	NP_001369164.1	A0A9L9PXL0
KCNQ2	NM_172106.3		c.*4G>A	3_prime_UTR	Exon 16 of 16	NP_742104.1	O43526-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.*4G>A	3_prime_UTR	Exon 17 of 17	ENSP00000352035.2	O43526-1
KCNQ2	ENST00000626839.2	TSL:1	c.*4G>A	3_prime_UTR	Exon 16 of 16	ENSP00000486706.1	O43526-2
KCNQ2	ENST00000344462.8	TSL:1	c.*4G>A	3_prime_UTR	Exon 16 of 16	ENSP00000339611.4	O43526-4

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00225

AC:

466

AN:

207336

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.000335

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000221

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000708

Gnomad NFE exome

AF:

0.00395

Gnomad OTH exome

AF:

0.00269

GnomAD4 exome

AF:

0.00264

AC:

3791

AN:

1434966

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

1812

AN XY:

712462

show subpopulations

African (AFR)

AF:

0.000332

AC:

AN:

33114

American (AMR)

AF:

0.00144

AC:

AN:

43132

Ashkenazi Jewish (ASJ)

AF:

0.000156

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39026

South Asian (SAS)

AF:

0.000993

AC:

AN:

84608

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

40112

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00312

AC:

3445

AN:

1104090

Other (OTH)

AF:

0.00210

AC:

125

AN:

59496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

225

450

676

901

1126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.00203

AC:

309

AN:

152260

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41554

American (AMR)

AF:

0.00242

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00348

AC:

237

AN:

68012

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00219

Hom.:

Bravo

AF:

0.00222

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Inborn genetic diseases (1)

KCNQ2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.45

(source)

DANN

Benign

0.85

PhyloP100

-3.3

Mutation Taster

=100/0

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