rs1801471

chr20-63407025-A-T

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.2238T>A(p.Pro746=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.933

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=-0.92).
• BP6: Variant 20-63407025-A-T is Benign according to our data. Variant chr20-63407025-A-T is described in ClinVar as [Benign]. Clinvar id is 129342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63407025-A-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.2238T>A	p.Pro746=	synonymous_variant	17/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.2238T>A	p.Pro746=	synonymous_variant	17/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11555 AN: 152174 Hom.: 586 Cov.: 33

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

GnomAD3 exomes AF: 0.108 AC: 14010 AN: 130086 Hom.: 927 AF XY: 0.112 AC XY: 8046 AN XY: 71550

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 SAS exome AF: 0.196

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.: 36 AF XY: 0.0991 AC XY: 66784 AN XY: 673660

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0948

Gnomad4 ASJ exome AF: 0.0470

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0932

Gnomad4 OTH exome AF: 0.0900

GnomAD4 genome AF: 0.0760 AC: 11567 AN: 152292 Hom.: 587 Cov.: 33 AF XY: 0.0780 AC XY: 5807 AN XY: 74470

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0696

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.0977

Gnomad4 NFE AF: 0.0990

Gnomad4 OTH AF: 0.0591

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -

Seizures, benign familial neonatal, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2016

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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Developmental and epileptic encephalopathy, 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.3
Dann	Benign	0.73

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

LitVar

Other links and lift over

dbSNP: rs1801471; hg19: chr20-62038378; COSMIC: COSV60546525; COSMIC: COSV60546525;