rs1057516096

Variant names:

• chr20-63439690-C-A
• rs1057516096
• NM_172107.4:c.835G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63439690-C-A
• chr20-63439690-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_172107.4(KCNQ2):​c.835G>T​(p.Gly279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.73
• Publications: 5 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 44 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63439689-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1701799.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to benign familial infantile epilepsy, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, 7, benign familial neonatal-infantile seizures, benign neonatal seizures, neonatal-onset developmental and epileptic encephalopathy, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, 1, neonatal encephalopathy with non-epileptic myoclonus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 20-63439690-C-A is Pathogenic according to our data. Variant chr20-63439690-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 369765.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.835G>T	p.Gly279Cys	missense_variant	Exon 6 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.835G>T	p.Gly279Cys	missense_variant	Exon 6 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

KCNQ2-related disorder Pathogenic:1

Sep 01, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ2 c.835G>T (p.Gly279Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250870 control chromosomes (gnomAD). c.835G>T has been reported in the literature in at least one individuals affected with KCNQ2-Related Disorders (e.g. Milh_2015). This report does not provide unequivocal conclusions about association of the variant with KCNQ2-Related Disorders. Automated patch clamp assays showed the variant had 4.8% peak current density relative to WT in transfected CHO cells stably expressing KCNQ3 (Vanoye_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25959266, 35104249). One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases Uncertain:1

Apr 20, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G279C variant (also known as c.835G>T), located in coding exon 6 of the KCNQ2 gene, results from a G to T substitution at nucleotide position 835. The glycine at codon 279 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in one individual in a cohort of individuals with recurrent seizures prior to one month of age, a normal metabolic profile, and a normal brain MRI (Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 7 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

EE (epileptic encephalopathy) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;D;D;D;D;D;D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;.;.;H;.;H;H;H
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.1	.;.;.;.;D;.;D;.;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.99
MutPred		0.87		Loss of ubiquitination at K283 (P = 0.0661);Loss of ubiquitination at K283 (P = 0.0661);Loss of ubiquitination at K283 (P = 0.0661);Loss of ubiquitination at K283 (P = 0.0661);Loss of ubiquitination at K283 (P = 0.0661);.;Loss of ubiquitination at K283 (P = 0.0661);.;Loss of ubiquitination at K283 (P = 0.0661);Loss of ubiquitination at K283 (P = 0.0661);Loss of ubiquitination at K283 (P = 0.0661);
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		-0.067	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057516096; hg19: chr20-62071043;