rs1060500602

Positions:

• chr20-63439650-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.875T>C​(p.Leu292Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L292F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.30

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr20-63439651-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2822011.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ 4.0411 (greater than the threshold 3.09). Trascript score misZ 3.6968 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.984
• PP5: Variant 20-63439650-A-G is Pathogenic according to our data. Variant chr20-63439650-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.875T>C	p.Leu292Pro	missense_variant	6/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.875T>C	p.Leu292Pro	missense_variant	6/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2019

This sequence change replaces leucine with proline at codon 292 of the KCNQ2 protein (p.Leu292Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy and has also been observed in cis with a second adjacent missense variant in an individual with epilepsy and/or neurodevelopmental disease (PMID: 29644095, 29655203). ClinVar contains an entry for this variant (Variation ID: 405208). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Jan 18, 2019

The c.875T>C (p.Leu292Pro) is a missense variant. This variant has not been reported in the literature. However, a variant classified as likely pathogenic has been reported in ClinVar at the same amino acid position (https://www.ncbi.nlm.nih.gov/clinvar/RCV000187943.1/). Additionally, this amino acid position lies within an established functional domain in KCNQ2. Multiple established pathogenic variants in KCNQ2 immediately surround position 292 (PMID: 24318194, 26007637; http://www.rikee.org/enter-kcnq2-variant-database). The variant is predicted to be damaging by in silico algorithms and is well conserved through evolution. Based on the combined evidence, this variant is classified as likely pathogenic. -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	.;.;D;D;D;T;D;D;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.7	.;.;.;.;D;.;D;.;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D
Polyphen		0.12	B;.;.;.;.;.;B;.;B;B;.
Vest4		0.94
MutPred		0.91		Loss of stability (P = 0.0698);Loss of stability (P = 0.0698);Loss of stability (P = 0.0698);Loss of stability (P = 0.0698);Loss of stability (P = 0.0698);.;Loss of stability (P = 0.0698);.;Loss of stability (P = 0.0698);Loss of stability (P = 0.0698);Loss of stability (P = 0.0698);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		1.0

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: rs1060500602; hg19: chr20-62071003;