20-63408536-T-A

Variant names:

• chr20-63408536-T-A
• rs118192237
• NM_172107.4:c.1764A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_172107.4(KCNQ2):​c.1764A>T​(p.Arg588Ser) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense, splice_region
• Scores: Splicing: ADA: 0.01118
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.15
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	NM_172107.4	MANE Select	c.1764A>T	p.Arg588Ser	missense splice_region	Exon 16 of 17	NP_742105.1
	KCNQ2	NM_001382235.1		c.1818A>T	p.Arg606Ser	missense splice_region	Exon 16 of 17	NP_001369164.1
	KCNQ2	NM_172106.3		c.1710A>T	p.Arg570Ser	missense splice_region	Exon 15 of 16	NP_742104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.1764A>T	p.Arg588Ser	missense splice_region	Exon 16 of 17	ENSP00000352035.2
	KCNQ2	ENST00000626839.2	TSL:1	c.1710A>T	p.Arg570Ser	missense splice_region	Exon 15 of 16	ENSP00000486706.1
	KCNQ2	ENST00000344462.8	TSL:1	c.1671A>T	p.Arg557Ser	missense splice_region	Exon 15 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Seizures, benign familial neonatal, 1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

BFNE (benign familial neonatal epilepsy)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.31	N
REVEL	Pathogenic	0.85
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.90	P
Vest4		0.98
MutPred		0.77		Loss of MoRF binding (P = 0.0155)
MVP		0.99
MPC		0.76
ClinPred		0.77	D
GERP RS		3.8
Varity_R		0.96
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.14
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: rs118192237; hg19: chr20-62039889;