20-63406982-C-G

Variant names:

• chr20-63406982-C-G
• rs587780366
• NM_172107.4:c.2281G>C

Variant summary

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

The NM_172107.4(KCNQ2):​c.2281G>C​(p.Ala761Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000727 in 1,375,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A761S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59
• 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.2281G>C	p.Ala761Pro	missense_variant	Exon 17 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.2281G>C	p.Ala761Pro	missense_variant	Exon 17 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375816 Hom.: 0 Cov.: 36 AF XY: 0.00000148 AC XY: 1 AN XY: 677706

African (AFR) AF: 0.00 AC: 0 AN: 31432

American (AMR) AF: 0.00 AC: 0 AN: 35592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24250

East Asian (EAS) AF: 0.00 AC: 0 AN: 35696

South Asian (SAS) AF: 0.00 AC: 0 AN: 78602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071756

Other (OTH) AF: 0.00 AC: 0 AN: 57380

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	.;T;T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	.;.;M;.;.;.
PhyloP100		3.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.77	.;.;N;.;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.13	.;.;T;.;T;.
Sift4G	Benign	0.22	T;.;T;T;T;T
Polyphen		0.99	D;.;D;.;D;D
Vest4		0.33
MutPred		0.25		.;.;Gain of loop (P = 0.0079);.;.;.;
MVP		0.78
MPC		1.6
ClinPred		0.72	D
GERP RS		5.0
Varity_R		0.52
gMVP		0.45
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs587780366; hg19: chr20-62038335;