chr20-63414925-G-C

Variant names:

• chr20-63414925-G-C
• rs1801545
• NM_172107.4:c.1503C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_172107.4(KCNQ2):​c.1503C>G​(p.Ala501Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0792 in 1,612,436 control chromosomes in the GnomAD database, including 5,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A501A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.092 (747 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4846 hom.)
• Consequence: KCNQ2 NM_172107.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.28
• Publications: 10 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-63414925-G-C is Benign according to our data. Variant chr20-63414925-G-C is described in ClinVar as Benign. ClinVar VariationId is 129337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	NM_172107.4	MANE Select	c.1503C>G	p.Ala501Ala	synonymous	Exon 13 of 17	NP_742105.1
	KCNQ2	NM_001382235.1		c.1449C>G	p.Ala483Ala	synonymous	Exon 12 of 17	NP_001369164.1
	KCNQ2	NM_172106.3		c.1449C>G	p.Ala483Ala	synonymous	Exon 12 of 16	NP_742104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.1503C>G	p.Ala501Ala	synonymous	Exon 13 of 17	ENSP00000352035.2
	KCNQ2	ENST00000626839.2	TSL:1	c.1449C>G	p.Ala483Ala	synonymous	Exon 12 of 16	ENSP00000486706.1
	KCNQ2	ENST00000344462.8	TSL:1	c.1413C>G	p.Ala471Ala	synonymous	Exon 12 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13907 AN: 151800 Hom.: 749 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0780

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.0679

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0720 AC: 17856 AN: 248164 AF XY: 0.0720

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0506

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0697

Gnomad NFE exome AF: 0.0853

Gnomad OTH exome AF: 0.0863

GnomAD4 exome AF: 0.0779 AC: 113733 AN: 1460518 Hom.: 4846 Cov.: 35 AF XY: 0.0771 AC XY: 56023 AN XY: 726608

African (AFR) AF: 0.146 AC: 4884 AN: 33474

American (AMR) AF: 0.0546 AC: 2444 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2809 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0439 AC: 3790 AN: 86246

European-Finnish (FIN) AF: 0.0699 AC: 3654 AN: 52270

Middle Eastern (MID) AF: 0.123 AC: 704 AN: 5702

European-Non Finnish (NFE) AF: 0.0815 AC: 90608 AN: 1111910

Other (OTH) AF: 0.0801 AC: 4834 AN: 60370

GnomAD4 genome AF: 0.0915 AC: 13905 AN: 151918 Hom.: 747 Cov.: 32 AF XY: 0.0901 AC XY: 6692 AN XY: 74242

African (AFR) AF: 0.137 AC: 5660 AN: 41414

American (AMR) AF: 0.0779 AC: 1191 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.0372 AC: 178 AN: 4788

European-Finnish (FIN) AF: 0.0679 AC: 719 AN: 10596

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0804 AC: 5461 AN: 67950

Other (OTH) AF: 0.101 AC: 212 AN: 2100

Alfa AF: 0.0634 Hom.: 126

Bravo AF: 0.0964

Asia WGS AF: 0.0250 AC: 90 AN: 3478

EpiCase AF: 0.0889

EpiControl AF: 0.0920

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Inborn genetic diseases Benign:1

Dec 31, 2015

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

Seizures, benign familial neonatal, 1 Benign:1

Apr 26, 2017

Athena Diagnostics

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	-0.82
CADD	Benign	0.014
DANN	Benign	0.43
PhyloP100		-4.3
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1801545; hg19: chr20-62046278;