rs980574000

Variant names:

• chr20-63407098-C-T
• rs980574000
• NM_172107.4:c.2165G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_172107.4(KCNQ2):​c.2165G>A​(p.Ser722Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,506 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.457
• 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14555922).

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.2165G>A	p.Ser722Asn	missense	Exon 17 of 17	NP_742105.1
	KCNQ2	NM_001382235.1		c.2219G>A	p.Ser740Asn	missense	Exon 17 of 17	NP_001369164.1
	KCNQ2	NM_172106.3		c.2111G>A	p.Ser704Asn	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.2165G>A	p.Ser722Asn	missense	Exon 17 of 17	ENSP00000352035.2
	KCNQ2	ENST00000626839.2	TSL:1	c.2111G>A	p.Ser704Asn	missense	Exon 16 of 16	ENSP00000486706.1
	KCNQ2	ENST00000344462.8	TSL:1	c.2072G>A	p.Ser691Asn	missense	Exon 16 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386506 Hom.: 0 Cov.: 36 AF XY: 0.00000293 AC XY: 2 AN XY: 683522

African (AFR) AF: 0.00 AC: 0 AN: 31696

American (AMR) AF: 0.00 AC: 0 AN: 36228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25060

East Asian (EAS) AF: 0.00 AC: 0 AN: 35822

South Asian (SAS) AF: 0.00 AC: 0 AN: 79888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076570

Other (OTH) AF: 0.00 AC: 0 AN: 57664

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 722 of the KCNQ2 protein (p.Ser722Asn). This variant is not present in population databases (gnomAD no frequency). 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: 461413). 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) indicates that this missense variant is not expected to disrupt KCNQ2 protein function with a negative predictive value of 95%. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.46
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.29
Sift	Benign	0.58	T
Sift4G	Benign	0.49	T
Polyphen		0.12	B
Vest4		0.055
MutPred		0.13		Loss of glycosylation at S722 (P = 0.0061)
MVP		0.61
MPC		0.61
ClinPred		0.13	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.10
Mutation Taster		=91/9	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: rs980574000; hg19: chr20-62038451;