20-63414925-G-C

Position:

• chr20-63414925-G-C

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 129337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63414925-G-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.1503C>G	p.Ala501Ala	synonymous_variant	13/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1503C>G	p.Ala501Ala	synonymous_variant	13/17	1	NM_172107.4	ENSP00000352035.2

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

GnomAD3 exomes AF: 0.0720 AC: 17856 AN: 248164 Hom.: 776 AF XY: 0.0720 AC XY: 9698 AN XY: 134642

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 SAS exome AF: 0.0417

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

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0546

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0439

Gnomad4 FIN exome AF: 0.0699

Gnomad4 NFE exome AF: 0.0815

Gnomad4 OTH exome AF: 0.0801

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

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0779

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0372

Gnomad4 FIN AF: 0.0679

Gnomad4 NFE AF: 0.0804

Gnomad4 OTH AF: 0.101

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Seizures, benign familial neonatal, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.014
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs1801545; hg19: chr20-62046278;