rs74315392

Variant names:

• chr20-63442482-G-A
• rs74315392
• NM_172107.4:c.740C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63442482-G-A
• chr20-63442482-G-C
• chr20-63442482-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_172107.4(KCNQ2):​c.740C>T​(p.Ser247Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 6.63

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S5 (size 20) in uniprot entity KCNQ2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• 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 seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 20-63442482-G-A is Pathogenic according to our data. Variant chr20-63442482-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205878.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=4}. Variant chr20-63442482-G-A is described in Lovd as [Pathogenic]. Variant chr20-63442482-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.740C>T	p.Ser247Leu	missense_variant	Exon 5 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.740C>T	p.Ser247Leu	missense_variant	Exon 5 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 31, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S5; This variant is associated with the following publications: (PMID: 26633542, 34120799, 33897753, 30530441, 30552426, 31199083, 31628766, 32863083, 32770121, 33333793, 28252636, 33659638, 33811133, 35729264, 35217970, 35401395, 29314763) -

Developmental and epileptic encephalopathy, 7 Pathogenic:2

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene, and are associated with developmental and epileptic encephalopathy 7 (MIM#613720) and benign neonatal seizures, 1 (MIM#121200), respectively (GeneReviews). There is currently no phenotypic correlation in terms of variant types or protein location (PMID: 31418850). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance however, this is only reported for patients with benign neonatal seizures (PMID: 25959266). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional pore domain in the fifth transmembrane region (PMID: 12742592, PMID: 33333793). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic in ClinVar, and de novo in multiple individuals with developmental and epileptic encephalopathy (DECIPHER, PMID: 33333793, PMID: 30552426). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Inborn genetic diseases Pathogenic:1

Oct 05, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Jul 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 247 of the KCNQ2 protein (p.Ser247Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 29314763, 32770121). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205878). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 32770121). This variant disrupts the p.Ser247 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12742592; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1 Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;D;D;D;T;D;D;.;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;H;.;H;H;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		0.63	P;.;.;.;.;.;P;.;P;P;.;.
Vest4		0.96
MutPred		0.63		Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);.;Loss of catalytic residue at S247 (P = 0.0242);.;Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);.;
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs74315392; hg19: chr20-62073835; COSMIC: COSV60436253; COSMIC: COSV60436253;