20-63445322-G-C

Position:

• chr20-63445322-G-C

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.430C>G​(p.Arg144Gly) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R144Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.0540

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 helix (size 28) 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63445321-C-T is described in Lovd as [Pathogenic].
• 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, 0.944
• PP5: Variant 20-63445322-G-C is Pathogenic according to our data. Variant chr20-63445322-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.430C>G	p.Arg144Gly	missense_variant	3/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.430C>G	p.Arg144Gly	missense_variant	3/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KCNQ2-related disorder Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 06, 2019	The KCNQ2 c.430C>G (p.Arg144Gly) variant is a missense variant that has been reported in a heterozygous state in one affected individual with a Rett-like phenotype (Vidal et al. 2019). The affected individual is specifically noted to have psychomotor delay and intellectual disability, but no developmental regression or breathing problems; no additional phenotypes were described. The p.Arg144Gly variant is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Two additional variants at the Arg144 residue have been described in literature, including p.Arg144Gln in an infant who presented with infantile spasms without seizures, global developmental delays, poor eye contact, no speech, inability to walk, and bilateral enlarged kidneys were also noted (Epi4K Consortium et al. 2013). The second variant at the Arg144 residue was identified in an affected individual with intellectual disability, but no additional phenotypes were described (Lelieveld et al. 2016). The p.Arg144Gly variant is located in the third segment of the transmembrane domain (Vidal et al. 2019). Based on the de novo state, absence from population frequency databases, and additional clinical evidence for the Arg144 residue, the p.Arg144Gly variant is classified as likely pathogenic for KCNQ2-related disorders. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as heterozygous, unknown inheritance, in a patient with Rett-like syndrome (PMID: 31105003). Two other missense changes affecting the same amino acid residue have been reported as de novo changes in patients with neurodevelopmental disorders (c.430C>T (p.Arg144Trp); PMID: 28628100) and seizure disorders including epileptic encephalopathy and infantile spasms (c.431G>A (p.Arg144Gln); PMID: 23934111, 29186148, 30174244). It is absent from the gnomAD population database and thus is presumed to be rare. The c.430C>G (p.Arg144Gly) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.430C>G (p.Arg144Gly) variant is classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2017

- -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Nov 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;D;D;D;D;D;.;.;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.27	N
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.1	.;.;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	.;.;.;.;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		0.98
MutPred		0.80		Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);.;Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);
MVP		1.0
MPC		3.2
ClinPred		1.0	D
GERP RS		-1.0
Varity_R		0.97
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: rs1555873985; hg19: chr20-62076675;