rs114095081

Variant names:

• chr8-132129575-G-A
• NM_004519.4:c.2306C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-132129575-G-A
• chr8-132129575-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004519.4(KCNQ3):​c.2306C>T​(p.Pro769Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P769H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37020946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.2306C>T	p.Pro769Leu	missense_variant	Exon 15 of 15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.2306C>T	p.Pro769Leu	missense_variant	Exon 15 of 15	1	NM_004519.4	ENSP00000373648.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;.;.;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.1	L;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;.;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.23	T;.;T;T;.
Sift4G	Benign	0.30	T;T;T;T;.
Polyphen		0.95	P;.;.;P;.
Vest4		0.067
MutPred		0.14		Gain of MoRF binding (P = 0.0825);.;.;.;.;
MVP		0.53
MPC		0.10
ClinPred		0.68	D
GERP RS		5.1
Varity_R		0.11
gMVP		0.33

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-133141822;