20-63439614-A-G

Variant names:

• chr20-63439614-A-G
• rs1057516100
• NM_172107.4:c.911T>C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.911T>C​(p.Phe304Ser) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F304F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.11

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 17 ACMG points.

• PM1: In a helix (size 41) in uniprot entity KCNQ2_HUMAN there are 12 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, 0.944
• PP5: Variant 20-63439614-A-G is Pathogenic according to our data. Variant chr20-63439614-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.911T>C	p.Phe304Ser	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.911T>C	p.Phe304Ser	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through a significant reduction in current amplitude and conductance-voltage relationship in KCNQ2 channels (PMID: 35857840); 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 S6 domain; This variant is associated with the following publications: (PMID: 28631195, 28867141, 31785789, 25959266, 23692823, 33057194, 35982159, 35857840) -

Sep 09, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM1, PM2, PM6, PP2, PP4 -

Developmental and epileptic encephalopathy, 7 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

EE (epileptic encephalopathy) -

Mar 25, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.911T>C;p.(Phe304Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 369771; PMID: 23692823; PMID: 25959266)PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans_2) - PM1. This variant is not present in population databases (rs1057516100- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 23692823; 25959266) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;D;D;D;T;D;D;.;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;M;.;M;M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.3	.;.;.;.;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
Polyphen		0.99	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.96
MutPred		0.71		Gain of catalytic residue at F304 (P = 0.1139);Gain of catalytic residue at F304 (P = 0.1139);Gain of catalytic residue at F304 (P = 0.1139);Gain of catalytic residue at F304 (P = 0.1139);Gain of catalytic residue at F304 (P = 0.1139);.;Gain of catalytic residue at F304 (P = 0.1139);.;Gain of catalytic residue at F304 (P = 0.1139);Gain of catalytic residue at F304 (P = 0.1139);Gain of catalytic residue at F304 (P = 0.1139);
MVP		1.0
MPC		4.2
ClinPred		1.0	D
GERP RS		2.9
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: rs1057516100; hg19: chr20-62070967;