20-63406982-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_172107.4(KCNQ2):​c.2281G>A​(p.Ala761Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000509 in 1,375,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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: 0.0000051 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.59
• Publications: 3 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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: Likely_benign. The variant received -4 ACMG points.

• 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 complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 7, neonatal encephalopathy with non-epileptic myoclonus, benign familial infantile epilepsy, malignant migrating partial seizures of infancy, seizures, benign familial neonatal, 1, benign familial neonatal-infantile seizures, benign neonatal seizures, seizures, benign familial neonatal, 2, undetermined early-onset epileptic encephalopathy, neonatal-onset developmental and epileptic encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3732198).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172107.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	NM_172107.4	MANE Select	c.2281G>A	p.Ala761Thr	missense	Exon 17 of 17	NP_742105.1	O43526-1
	KCNQ2	NM_001382235.1		c.2335G>A	p.Ala779Thr	missense	Exon 17 of 17	NP_001369164.1	A0A9L9PXL0
	KCNQ2	NM_172106.3		c.2227G>A	p.Ala743Thr	missense	Exon 16 of 16	NP_742104.1	O43526-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.2281G>A	p.Ala761Thr	missense	Exon 17 of 17	ENSP00000352035.2	O43526-1
	KCNQ2	ENST00000626839.2	TSL:1	c.2227G>A	p.Ala743Thr	missense	Exon 16 of 16	ENSP00000486706.1	O43526-2
	KCNQ2	ENST00000344462.8	TSL:1	c.2188G>A	p.Ala730Thr	missense	Exon 16 of 16	ENSP00000339611.4	O43526-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000782 AC: 1 AN: 127898 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000509 AC: 7 AN: 1375816 Hom.: 0 Cov.: 36 AF XY: 0.00000590 AC XY: 4 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: 0.0000127 AC: 1 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: 0.00000467 AC: 5 AN: 1071756

Other (OTH) AF: 0.0000174 AC: 1 AN: 57380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Developmental and epileptic encephalopathy (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	M
PhyloP100		3.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.51
Sift	Benign	0.19	T
Sift4G	Benign	0.36	T
Polyphen		0.98	D
Vest4		0.24
MutPred		0.26		Gain of loop (P = 0.0166)
MVP		0.64
MPC		0.80
ClinPred		0.36	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.33
Mutation Taster		=88/12	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; COSMIC: COSV60554335; COSMIC: COSV60554335;