20-63414927-C-T

Variant names:

• chr20-63414927-C-T
• rs1057516118
• NM_172107.4:c.1501G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_172107.4(KCNQ2):​c.1501G>A​(p.Ala501Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A501P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 0 publications found

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]

KCNQ2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• neonatal encephalopathy with non-epileptic myoclonus

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neonatal-onset developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 benign familial infantile epilepsy, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, 7, benign familial neonatal-infantile seizures, benign neonatal seizures, neonatal-onset developmental and epileptic encephalopathy, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, 1, neonatal encephalopathy with non-epileptic myoclonus.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.1501G>A	p.Ala501Thr	missense_variant	Exon 13 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1501G>A	p.Ala501Thr	missense_variant	Exon 13 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;.;T;T;D;T;D;T;.;.;T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	.;.;.;.;.;.;M;.;.;.;.
PhyloP100		2.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	.;.;.;.;N;.;N;.;N;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.36	.;.;.;.;T;.;T;.;T;.;.
Sift4G	Benign	0.39	T;T;T;T;T;.;T;T;T;T;T
Polyphen		0.57	P;.;.;.;.;.;P;.;P;P;.
Vest4		0.45
MutPred		0.34		.;.;.;.;.;.;Gain of phosphorylation at A501 (P = 0.0405);.;.;.;.;
MVP		0.85
MPC		1.1
ClinPred		0.77	D
GERP RS		5.2
PromoterAI		-0.033	Neutral
Varity_R		0.14
gMVP		0.58
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057516118; hg19: chr20-62046280;