rs118192186

Variant names:

• chr20-63472462-A-C
• rs118192186
• NM_172107.4:c.2T>G

Your query was ambiguous. Multiple possible variants found:

• chr20-63472462-A-C
• chr20-63472462-A-G
• chr20-63472462-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_172107.4(KCNQ2):​c.2T>G​(p.Met1?) variant causes a start lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 105 pathogenic variants. Next in-frame start position is after 174 codons. Genomic position: 63444829. Lost 0.199 part of the original CDS.
• PS1: Another start lost variant in NM_172107.4 (KCNQ2) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.2T>G	p.Met1?	start_lost	Exon 1 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.2T>G	p.Met1?	start_lost	Exon 1 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150862 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 150862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73642

African (AFR) AF: 0.00 AC: 0 AN: 41126

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 4936

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67642

Other (OTH) AF: 0.00 AC: 0 AN: 2086

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.35	.;.;T;T;T;T;.;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		2.6
PROVEAN	Benign	-2.2	.;.;.;.;N;N;N;N;N
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;.;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;.;.;.;.;D;D;D;.
Vest4		0.73
MutPred		0.99		Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);Gain of MoRF binding (P = 0.0391);
MVP		0.91
ClinPred		1.0	D
GERP RS		2.1
PromoterAI		-0.13	Neutral
Varity_R		0.95
gMVP		0.95
Mutation Taster		=0/200	disease causing

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: rs118192186; hg19: chr20-62103815;