rs1554622023

Variant names:

• chr8-132134290-C-T
• rs1554622023
• NM_004519.4:c.1799G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004519.4(KCNQ3):​c.1799G>A​(p.Arg600Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35
• Publications: 0 publications found

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• self-limited familial neonatal epilepsy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.1799G>A	p.Arg600Lys	missense splice_region	Exon 13 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.1439G>A	p.Arg480Lys	missense splice_region	Exon 13 of 15	NP_001191753.1	O43525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.1799G>A	p.Arg600Lys	missense splice_region	Exon 13 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000521134.6	TSL:2	c.1439G>A	p.Arg480Lys	missense splice_region	Exon 13 of 15	ENSP00000429799.1	O43525-2
	KCNQ3	ENST00000638588.1	TSL:5	c.1472G>A	p.Arg491Lys	missense splice_region	Exon 13 of 15	ENSP00000491940.1	A0A1W2PQ71

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460582 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726746

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111092

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Benign neonatal seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.55
Sift	Benign	0.35	T
Sift4G	Benign	0.38	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.41		Gain of ubiquitination at R600 (P = 0.0014)
MVP		0.83
MPC		0.50
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.53
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554622023; hg19: chr8-133146537;