20-63439610-G-T

Position:

• chr20-63439610-G-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.915C>A​(p.Phe305Leu) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F305S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: -2.11

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 21 ACMG points.

• PS1: Transcript NM_172107.4 (KCNQ2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 461423
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr20-63439611-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2818350.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 20-63439610-G-T is Pathogenic according to our data. Variant chr20-63439610-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205887.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.915C>A	p.Phe305Leu	missense_variant	6/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.915C>A	p.Phe305Leu	missense_variant	6/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/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

Mar 18, 2019

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. A different variant (c.913T>C) giving rise to the same protein effect observed here (p.Phe305Leu) has been determined to be pathogenic (PMID:27779742, 25473036). This suggests that this variant is also likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has been observed in an individual affected with neonatal epileptic encephalopathy (PMID: 24107868). ClinVar contains an entry for this variant (Variation ID: 205887). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 305 of the KCNQ2 protein (p.Phe305Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2013

p.Phe305Leu (TTC>TTA): c.915 C>A in exon 6 of the KCNQ2 gene (NM_172107.2)The Phe305Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Phe305Leu in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative as both Phenylalanine and Leucine are uncharged, non-polar amino acid residues. However, Phe305Leu alters a conserved position in a transmembrane domain in the KCNQ2 protein and other missense mutations in this region of the protein have been identified in patients with benign familial neonatal seizures (Steinlein et al., 2007; Singh et al., 1998). In addition, multiple in-silico algorithms predict it may be damaging to the structure/function of the protein. Therefore, based on the currently available information, Phe305Leu is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s). -

Developmental and epileptic encephalopathy, 7 Other:1

not provided, no classification provided

literature only

GeneReviews

-

EE (epileptic encephalopathy) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	1.5
DANN	Uncertain	0.99
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.032	D;D;D;D;D;.;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;D;.;D;P;.
Vest4		0.95
MutPred		0.58		Gain of catalytic residue at F305 (P = 0.0621);Gain of catalytic residue at F305 (P = 0.0621);Gain of catalytic residue at F305 (P = 0.0621);Gain of catalytic residue at F305 (P = 0.0621);Gain of catalytic residue at F305 (P = 0.0621);.;Gain of catalytic residue at F305 (P = 0.0621);.;Gain of catalytic residue at F305 (P = 0.0621);Gain of catalytic residue at F305 (P = 0.0621);Gain of catalytic residue at F305 (P = 0.0621);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		-5.4
Varity_R		0.91
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs775918190; hg19: chr20-62070963;