20-63444712-G-T

Variant names:

• chr20-63444712-G-T
• rs118192203
• NM_172107.4:c.637C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172107.4(KCNQ2):​c.637C>A​(p.Arg213Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000692 in 1,444,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• Publications: 36 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

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.637C>A	p.Arg213Arg	synonymous	Exon 4 of 17	NP_742105.1
	KCNQ2	NM_001382235.1		c.637C>A	p.Arg213Arg	synonymous	Exon 4 of 17	NP_001369164.1
	KCNQ2	NM_172106.3		c.637C>A	p.Arg213Arg	synonymous	Exon 4 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.637C>A	p.Arg213Arg	synonymous	Exon 4 of 17	ENSP00000352035.2
	KCNQ2	ENST00000626839.2	TSL:1	c.637C>A	p.Arg213Arg	synonymous	Exon 4 of 16	ENSP00000486706.1
	KCNQ2	ENST00000344462.8	TSL:1	c.637C>A	p.Arg213Arg	synonymous	Exon 4 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000449 AC: 1 AN: 222576 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444804 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716746

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.00 AC: 0 AN: 42156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104382

Other (OTH) AF: 0.00 AC: 0 AN: 59780

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		6.7
PromoterAI		-0.0089	Neutral

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: rs118192203; hg19: chr20-62076065;