rs74582884
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_004519.4(KCNQ3):c.1720C>T(p.Pro574Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,612,916 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_004519.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00246 AC: 374AN: 152090Hom.: 4 Cov.: 31
GnomAD3 exomes AF: 0.00212 AC: 534AN: 251432Hom.: 1 AF XY: 0.00206 AC XY: 280AN XY: 135884
GnomAD4 exome AF: 0.00277 AC: 4049AN: 1460708Hom.: 9 Cov.: 30 AF XY: 0.00274 AC XY: 1990AN XY: 726748
GnomAD4 genome AF: 0.00246 AC: 374AN: 152208Hom.: 4 Cov.: 31 AF XY: 0.00253 AC XY: 188AN XY: 74412
ClinVar
Submissions by phenotype
not provided Benign:5
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Published functional studies demonstrate no damaging effect, specifically, voltage clamp analysis revealed no significant reduction in potassium current as compared to wildtype (Neubauer et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28351718, 20981092, 18625963, 19344764, 23596459, 25784856, 28488083, 27875746, 29948376) -
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KCNQ3: PM5, BS2 -
Seizures, benign familial neonatal, 2 Benign:4Other:1
Allele is present at 0.3% in non-Finnish Europeans and 0.2% in Latinos (gnomAD). Overrepresented (p=0.008) in idiopathic generalized epilepsies (8/455 persons). Detected in other complex phenotypes; in 4 persons with rolandic epilepsy and in 1 with rolandic epilepsy and moderate psychomotor delay; in 3 persons with autism spectrum disorders and no additional neurologic features -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not specified Benign:3
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Inborn genetic diseases Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
KCNQ3-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign Neonatal Epilepsy Benign:1
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Benign neonatal seizures Benign:1
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Intellectual disability Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at