8-132134369-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004519.4(KCNQ3):​c.1720C>G​(p.Pro574Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,744 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P574S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

8
5
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ3NM_004519.4 linkc.1720C>G p.Pro574Ala missense_variant Exon 13 of 15 ENST00000388996.10 NP_004510.1 O43525-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ3ENST00000388996.10 linkc.1720C>G p.Pro574Ala missense_variant Exon 13 of 15 1 NM_004519.4 ENSP00000373648.3 O43525-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460744
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726770
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;.;.;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Uncertain
0.73
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.9
L;.;.;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.4
N;.;N;N;.
REVEL
Pathogenic
0.73
Sift
Benign
0.12
T;.;T;T;.
Sift4G
Benign
0.11
T;T;T;T;.
Polyphen
1.0
D;.;.;D;.
Vest4
0.65
MutPred
0.45
Loss of glycosylation at P574 (P = 0.044);.;.;Loss of glycosylation at P574 (P = 0.044);.;
MVP
0.78
MPC
0.50
ClinPred
0.94
D
GERP RS
5.5
Varity_R
0.16
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.24
Position offset: -43

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: chr8-133146616; API