rs146492238

chr20-63415080-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172107.4(KCNQ2):c.1348G>A(p.Val450Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,605,360 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.05

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNQ2
• BP4: Computational evidence support a benign effect (MetaRNN=0.005745232).
• BP6: Variant 20-63415080-C-T is Benign according to our data. Variant chr20-63415080-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63415080-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000926 (141/152260) while in subpopulation NFE AF= 0.000559 (38/68024). AF 95% confidence interval is 0.000418. There are 2 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.1348G>A	p.Val450Met	missense_variant	13/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1348G>A	p.Val450Met	missense_variant	13/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00164 AC: 394 AN: 239962 Hom.: 5 AF XY: 0.00155 AC XY: 204 AN XY: 131212

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000750

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00111 AC: 1618 AN: 1453100 Hom.: 9 Cov.: 35 AF XY: 0.00108 AC XY: 782 AN XY: 723304

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0273

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000666

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74430

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00231 Hom.: 6

Bravo AF: 0.00112

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00126 AC: 153

EpiCase AF: 0.00120

EpiControl AF: 0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNQ2: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2017

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. -

KCNQ2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.15	T;T;T;T;T;.;T;T;T;T
Polyphen		0.094	B;.;.;.;.;.;B;.;B;P
Vest4		0.18
MVP		0.57
MPC		0.64
ClinPred		0.0075	T
GERP RS		3.3
Varity_R		0.045
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs146492238; hg19: chr20-62046433; COSMIC: COSV105236751; COSMIC: COSV105236751;