20-63407308-G-C

Variant names:

• chr20-63407308-G-C
• rs770730662
• NM_172107.4:c.1955C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_172107.4(KCNQ2):​c.1955C>G​(p.Pro652Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,595,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P652L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.09
• Publications: 2 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_benign. The variant received -5 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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3717454).
• BP6: Variant 20-63407308-G-C is Benign according to our data. Variant chr20-63407308-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430045.
• BS2: High AC in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	NM_172107.4	MANE Select	c.1955C>G	p.Pro652Arg	missense	Exon 17 of 17	NP_742105.1
	KCNQ2	NM_001382235.1		c.2009C>G	p.Pro670Arg	missense	Exon 17 of 17	NP_001369164.1
	KCNQ2	NM_172106.3		c.1901C>G	p.Pro634Arg	missense	Exon 16 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.1955C>G	p.Pro652Arg	missense	Exon 17 of 17	ENSP00000352035.2
	KCNQ2	ENST00000626839.2	TSL:1	c.1901C>G	p.Pro634Arg	missense	Exon 16 of 16	ENSP00000486706.1
	KCNQ2	ENST00000344462.8	TSL:1	c.1862C>G	p.Pro621Arg	missense	Exon 16 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000212 AC: 5 AN: 236050 AF XY: 0.0000154

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1443682 Hom.: 0 Cov.: 36 AF XY: 0.00000418 AC XY: 3 AN XY: 718028

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.0000448 AC: 2 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109818

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.0000723 AC: 3 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 652 of the KCNQ2 protein (p.Pro652Arg). This variant is present in population databases (rs770730662, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 430045). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1

Mar 12, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the KCNQ2 gene. The P652R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P652R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P652R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Uncertain:1

Jan 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Dec 22, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.49
Sift	Benign	0.30	T
Sift4G	Benign	0.31	T
Polyphen		0.029	B
Vest4		0.059
MutPred		0.61		Loss of catalytic residue at P651 (P = 0.0099)
MVP		0.58
MPC		0.71
ClinPred		0.089	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.39
Mutation Taster		=86/14	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: rs770730662; hg19: chr20-62038661;