chr20-63442449-T-C

Variant names:

• chr20-63442449-T-C
• rs118192207
• NM_172107.4:c.773A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_172107.4(KCNQ2):​c.773A>G​(p.Asn258Ser) variant causes a missense change involving the alteration of a 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N258D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.84
• Publications: 14 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 30 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63442450-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4071957.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.773A>G	p.Asn258Ser	missense_variant	Exon 5 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.773A>G	p.Asn258Ser	missense_variant	Exon 5 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

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). FS (febrile seizures) at 10 months. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Benign	-0.044
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;M;.;M;M;M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	.;.;.;.;D;.;D;.;D;D;D;.
Sift4G	Uncertain	0.045	D;T;T;T;T;.;D;D;D;D;T;T
Polyphen		0.0020	B;.;.;.;.;.;B;.;B;B;.;.
Vest4		0.73
MutPred		0.81		Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);.;Gain of disorder (P = 0.0544);.;Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);.;
MVP		0.95
MPC		1.3
ClinPred		0.91	D
GERP RS		3.4
Varity_R		0.57
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs118192207; hg19: chr20-62073802;