NM_004519.4:c.49G>C

Variant names:

• chr8-132480484-C-G
• rs1355500787
• NM_004519.4:c.49G>C

Variant summary

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

The NM_004519.4(KCNQ3):​c.49G>C​(p.Asp17His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,051,726 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D17N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• 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):

• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

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 (MetaRNN=0.17889547).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.49G>C	p.Asp17His	missense	Exon 1 of 15	NP_004510.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.49G>C	p.Asp17His	missense	Exon 1 of 15	ENSP00000373648.3
	KCNQ3	ENST00000519445.5	TSL:5	c.49G>C	p.Asp17His	missense	Exon 1 of 15	ENSP00000428790.1
	KCNQ3	ENST00000519589.1	TSL:2	n.-174G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000285 AC: 3 AN: 1051726 Hom.: 0 Cov.: 31 AF XY: 0.00000398 AC XY: 2 AN XY: 502370

African (AFR) AF: 0.00 AC: 0 AN: 21144

American (AMR) AF: 0.00 AC: 0 AN: 7066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11982

East Asian (EAS) AF: 0.00 AC: 0 AN: 22130

South Asian (SAS) AF: 0.00 AC: 0 AN: 20372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2820

European-Non Finnish (NFE) AF: 0.00000331 AC: 3 AN: 905980

Other (OTH) AF: 0.00 AC: 0 AN: 40730

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.55
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.024	D
Sift4G	Benign	0.12	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.22		Gain of MoRF binding (P = 0.071)
MVP		0.61
MPC		1.1
ClinPred		0.078	T
GERP RS		2.8
PromoterAI		0.013	Neutral
Varity_R		0.12
gMVP		0.26
Mutation Taster		=93/7	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: rs1355500787; hg19: chr8-133492731;